Epileptiform EEG abnormalities in children with language regression.

The authors examined the records of 149 children with language regression (LR) who had overnight EEG monitoring. Children with isolated LR had a higher frequency of epileptiform abnormalities (60%) than those with LR in the context of autistic regression (31%, p = 0.002) and also a higher rate of clinical seizures (33% vs 8%, p < 0.001). EEG abnormalities in the LR only group were also more prominent. This suggests two subtypes of language regression.

[Neurodevelopmental disorders and epilepsy]. / Trastornos del neurodesarrollo y epilepsia.

INTRODUCTION AND DEVELOPMENT: Neurodevelopmental disorders and the epilepsies share common etiologies and pathologies. The severity of impairment and the variety of symptoms associated with neurodevelopmental disorders or with particular epilepsy syndromes reflect focal or global, structural or functional dysfunction of neuronal networks. The complex relationship between neurodevelopmental disorders and epilepsy is secondary to common factors that include genetics, cognition, motor and language function. The epileptic encephalopathies are associated with regression or slowing of cognitive, language or behavior and the accepted working hypothesis is that this is a direct consequence of the seizures or of the interictal epileptiform activity, as opposed to the associated medical condition. The evidence that recurrent seizures or abnormal electrical activity can cause specific cognitive, language or behavioral abnormalities even in accepted epileptic encephalopathies is still controversial. Data from animal studies and the clinical experience from epileptic encephalopathies of early life imply that there are developmental time windows crucial to the type of epilepsy syndrome and to cognitive and behavioral outcome. CONCLUSION: The management of children in whom a neurodevelopmental disorder coexists with epilepsy is a difficult problem that requires a multidisciplinary approach that addresses both the epilepsy and the specific cognitive or behavioral problem and is tailored to the needs of the individual child.

Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis.

Pigmentary type of orthochromatic leukodystrophy (POLD) is an adult-onset leukodystrophy, characterized pathologically by the presence of glial and microglial cytoplasmic pigment inclusions. The complete phenotype, genotype and pathogenetic mechanisms in POLD have not been elucidated. We followed for 18 years a woman with autopsy-proven POLD, who presented with 'frontal' dementia and spasticity. Her further course was marked by progressive mutism, apraxia and seizures. Her sister had died of the same disease after a much more rapidly progressing course. These sisters had primary infertility with pathologic evidence of streak ovaries. Diagnosis was confirmed in both cases by post-mortem examination. POLD is a rare cause of adult-onset leukodystrophy presenting with dementia. Ovarian dysgenesis is extremely rare in the absence of demonstrable chromosomal abnormalities and extends the clinical spectrum of POLD.

Etiology and pathophysiology of autistic behavior: clues from two cases with an unusual variant of neuroaxonal dystrophy.

Two unrelated individuals with autistic behavior had numerous swollen axon terminals (spheroids) located in specific brain regions relevant to their behavioral symptoms. Spheroids are characteristic of neuroaxonal dystrophy, but the clinical profile and anatomic distribution of the lesions in these two patients differed from those of previously described patients with neuroaxonal dystrophy. Spheroids were numerous in the sensory nuclei of the spinal cord and medulla, specific nuclei and the reticular formation of the brainstem tegmentum, hypothalamus, anterior and dorsomedial thalamus, hippocampus, and cingulate and orbitofrontal cortices. Spheroids were sparse in the primary and association cortices and basal ganglia and absent in the hemispheric white matter. Cerebellar atrophy was present in both cases but associated with spheroids in only one case. These cases represent a new variant of neuroaxonal dystrophy in which behavioral symptoms characteristic of autism dominated the clinical picture. Neuroaxonal dystrophy should be included in the list of diseases that may be found in persons with autism.

Predictors and correlates of adaptive functioning in children with developmental disorders.

Autism is a developmental disorder marked by impairments in socialization, communication, and perseverative behavior and is associated with cognitive impairment and deficits in adaptive functioning. Research has consistently demonstrated that children with autism have deficits in adaptive functioning more severe than their cognitive deficits. This study investigates the correlates and predictors of adaptive functioning as measured by the Vineland Adaptive Behavior Scales in high- and low-functioning children with autism and their age and nonverbal IQ matched controls. Thirty-five 9-year-old children with high-functioning autism (HAD) were compared with 31 age-matched children with developmental language disorder (DLD), and 40 9-year-old children with low-functioning autism (LAD) were compared with 17 age-matched children with low IQ on adaptive functioning, IQ, autistic symptomology, and tests of language and verbal memory. Results indicate that both groups with autism were significantly impaired compared to their matched controls on Socialization and Daily Living, but not Communication and that these impairments were more pronounced in the HAD group than in the LAD group. Adaptive behavior was strongly correlated with autistic symptomology only in the HAD group. Regression analyses indicated that IQ was strongly predictive of adaptive behavior in both low-functioning groups, but tests of language and verbal memory predicted adaptive behavior in the higher functioning groups. Results suggest that IQ may act as a limiting factor for lower functioning children but higher functioning children are impaired by specific deficits, including autistic symptomology and impaired language and verbal memory.

Autistic disorder versus other pervasive developmental disorders in young children: same or different?

Eighteen preschool children diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised (DSM III-R) as having Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) were compared to 176 children with DSM III-R Autistic Disorder (AD), and to 311 non-autistic children with developmental language disorders (DLD) (N = 201) or low IQ (N = 110). All children were partitioned into "high" and "low" cognitive subgroups at a nonverbal IQ of 80. Within cognitive subgroups, the 18 PDD-NOS children did not differ significantly from either the DLD or the AD children in verbal and adaptive skills and obtained scores intermediate between those of these groups. The PDD-NOS did not differ from the AD children in maladaptive behaviors. Both the PDD-NOS and AD children had many more of these behaviors than the non-autistic comparison groups. Children in the "high" and "low" cognitive subgroups of AD, but not of PDD-NOS, differed substantially on most measures, with the children with lower cognitive scores significantly more impaired on all measures. Similarity of PDD-NOS children to AD children in maladaptive behaviors and an intermediate position between autistic and non-autistic groups on virtually all measures explains the difficulty clinicians encounter in classifying children with PDD and raises questions about the specificity of these diagnostic subtypes of the autistic spectrum.

Language regression in childhood.

Language regression is observed both in autistic regression and as part of acquired epileptic aphasia (Landau-Kleffner Syndrome). We prospectively identified 177 children with language regression at four major medical centers, and their clinical characteristics were recorded. Their mean age at regression was 22.8 months. The mean time-to-specialist referral was 38 months of age. Most children (88%) met criteria for autism or manifested autistic features. Males (P = 0.02) and children less than 3 years of age who regressed (P = 0.016) had a higher probability of developing autistic behaviors. Seizures were more common in children who regressed after they reached 3 years of age (P < 0.001), and children with seizures were less likely to have associated autistic regression (P < 0.001). Electroencephalogram abnormalities were reported in 37% of patients and were more common in children with seizures (P < 0.001). At last follow-up, language function was impaired in 88% of the children, although some improvement was noted in 57%. We conclude that the loss of previously acquired language at any age, even if that language only includes a few words or communicative gestures, is often associated with a more global regression in cognition and/or behavior and has serious implications for future function. Early identification and referral of these children is necessary to allow for diagnosis and intervention.

Executive functioning in high-functioning children with autism.

Executive functioning was investigated in 34 children (24 boys and 10 girls) with developmental language disorder (DLD) and 21 children (18 boys and 3 girls) with high-functioning autistic disorder (HAD) matched on Full Scale IQ, Nonverbal IQ, age (mean age 9 year, 1 month), and SES. The DLD group had a Verbal IQ that was 10 points higher than the HAD group. These children were given the Wisconsin Card Sorting Test (WCST), the Mazes subtest from the WISC-R, the Underlining test, and the Rapid Automatized Naming test. In addition, these children were given the Vineland Scales of Adaptive Functioning and the Wing Diagnostic Symptom Checklist in order to assess severity of autistic symptomatology. Results indicated that the only significant difference between the two groups on the cognitive tasks was perseverative errors on the WCST; there was no significant difference on total number of categories achieved or total number of errors on the WCST or on the other executive function measures. There was also significant overlap in the scores between the two groups and the difference in perseverative errors was no longer significant when Verbal IQ was partialled out. Executive functioning was strongly related to all IQ variables in the DLD group and particularly related to Verbal IQ in the HAD group. Although there was a relationship in the HAD group between executive functioning and adaptive functioning, as well as between executive functioning and autistic symptomatology, these relationships were generally no longer significant in the HAD group after the variance due to Verbal IQ was accounted for. The results are interpreted to indicate that although impaired executive functioning is a commonly associated feature of autism, it is not universal in autism and is unlikely to cause autistic behaviors or deficits in adaptive function.

Xeroderma pigmentosum/cockayne syndrome complex: first neuropathological study and review of eight other cases.

This is the first detailed description of the neuropathology of a patient with xeroderma pigmentosum/Cockayne syndrome complex (XP/CS). This 6-year-old boy's clinical course, followed from infancy to death, is compared with that of the eight other known cases of XP/CS. Normal at birth, he developed the cutaneous sun sensitivity of XP in infancy and the infantile CS phenotype in early childhood. He had the characteristic CS facies, cachexia, failure of somatic and brain growth, spasticity, ataxia, pigmentary retinopathy, hearing loss, mixed peripheral neuropathy, and myopathy. Like his clinical phenotype, the neuropathology was also that of CS despite an XPG genotype. His brain weighed 350 grams (considerably less than the expected weight at birth) and revealed hydrocephalus, tigroid-type demyelination, dystrophic calcification and widespread neuronal loss and gliosis with hyperchromatic glial and endothelial nuclei. Peripheral nerve showed myelinopathy with axonal degeneration, and skeletal muscle had mixed myopathic and neuropathic features. Ophthalmic pathology disclosed cataracts, iris and ciliary body atrophy, inner retinal atrophy and gliosis, retinal pigment epithelial atrophy, and optic nerve atrophy. Molecular studies, which have appeared elsewhere, do not provide full understanding of the pathophysiology of the postnatal growth failure, cachexia, precocious aging, selectivity of tissues affected (such as myelinated axons), and other manifestations of this devastating illness.

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society.

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Subgroups of children with autism by cluster analysis: a longitudinal examination.

OBJECTIVES: A hierarchical cluster analysis was conducted using a sample of 138 school-age children with autism. The objective was to examine (1) the characteristics of resulting subgroups, (2) the relationship of these subgroups to subgroups of the same children determined at preschool age, and (3) preschool variables that best predicted school-age functioning. METHOD: Ninety-five cases were analyzed. RESULTS: Findings support the presence of 2 subgroups marked by different levels of social, language, and nonverbal ability, with the higher group showing essentially normal cognitive and behavioral scores. The relationship of high- and low-functioning subgroup membership to levels of functioning at preschool age was highly significant. CONCLUSIONS: School-age functioning was strongly predicted by preschool cognitive functioning but was not strongly predicted by preschool social abnormality or severity of autistic symptoms. The differential outcome of the 2 groups shows that high IQ is necessary but not sufficient for optimal outcome in the presence of severe language impairment.

Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease.

OBJECTIVE: To describe a case with a new genetic variant of type 3 Gaucher disease presenting with stimulus-sensitive and action myoclonus in the presence of selective dentate abnormalities. DESIGN: Clinical, pathologic, and molecular genetic studies. SETTING: Medical school departments. PATIENT: A 6-year-old girl with type 3 Gaucher disease experienced progressively crippling generalized stimulus-sensitive and action myoclonus. Repeated electroencephalographic examination did not show cortical activity associated with the myoclonus, suggesting its subcortical origin. Neuropathological examination revealed selective degeneration of the cerebellar dentate nucleus and dentatorubrothalamic pathway in the face of essentially complete lack of storage in the brain. Mutation analysis identified the following 2 mutant alleles: one with a V394L mutation and the other with the lesion RecTL (D409H + L444P + A456P + V460V), which resulted from a recombination event, with the pseudogene located 16 kilobases downstream from the structural gene. CONCLUSION: Given the restricted abnormalities, this genetically unique case provides insight into the pathogenesis of myoclonus and suggests a prominent role for the cerebellar dentate nucleus in its genesis.

The influence of premorbid language skills and behavior on language recovery in children with verbal auditory agnosia.

Previous studies of children with Landau-Kleffner syndrome and related language-epilepsy syndromes have focused on the relationship of seizure control to language recovery. We examined the effect of premorbid language skills and behavior, as well as some characteristics of clinical seizures and electroencephalograms, on language recovery in a retrospective study of 67 children with the severe receptive and expressive language disorder, verbal auditory agnosia. Fifty-eight percent of these children had seizures, 76% were autistic, and 24% had a history of language regression after showing previously normal language skills. The duration of language loss was not influenced by the persistence of clinical seizures. Premorbid language and behavior were more predictive of language recovery in these children. Most children with normal early language (acquired verbal auditory agnosia) had onset of language loss after age 3 years, in contrast to those with abnormal early language. Children with acquired verbal auditory agnosia were more likely to show fluctuations in language skills than those in other groups. Autistic children were more likely to begin having seizures before age 3 years, and had a longer duration of language loss and lower educational placement at time of last follow-up than those with normal behavior. This study emphasizes the importance of assessing premorbid language and behavior in predicting recovery of language skills in children with language-epilepsy syndromes.

Cockayne syndrome and xeroderma pigmentosum.

OBJECTIVES: To review genetic variants of Cockayne syndrome (CS) and xeroderma pigmentosum (XP), autosomal recessive disorders of DNA repair that affect the nervous system, and to illustrate them by the first case of xeroderma pigmentosum-Cockayne syndrome (XP-CS) complex to undergo neuropathologic examination. METHODS: Published reports of clinical, pathologic, and molecular studies of CS, XP neurologic disease, and the XP-CS complex were reviewed, and a ninth case of XP-CS is summarized. RESULTS: CS is a multisystem disorder that causes both profound growth failure of the soma and brain and progressive cachexia, retinal, cochlear, and neurologic degeneration, with a leukodystrophy and demyelinating neuropathy without an increase in cancer. XP presents as extreme photosensitivity of the skin and eyes with a 1000-fold increased frequency of cutaneous basal and squamous cell carcinomas and melanomas and a small increase in nervous system neoplasms. Some 20% of patients with XP incur progressive degeneration of previously normally developed neurons resulting in cortical, basal ganglia, cerebellar, and spinal atrophy, cochlear degeneration, and a mixed distal axonal neuropathy. Cultured cells from patients with CS or XP are hypersensitive to killing by ultraviolet (UV) radiation. Both CS and most XP cells have defective DNA nucleotide excision repair of actively transcribing genes; in addition, XP cells have defective repair of the global genome. There are two complementation groups in CS and seven in XP. Patients with the XP-CS complex fall into three XP complementation groups. Despite their XP genotype, six of nine individuals with the XP-CS complex, including the boy we followed up to his death at age 6, had the typical clinically and pathologically severe CS phenotype. Cultured skin and blood cells had extreme sensitivity to killing by UV radiation, DNA repair was severely deficient, post-UV unscheduled DNA synthesis was reduced to less than 5%, and post-UV plasmid mutation frequency was increased. CONCLUSIONS: The paradoxical lack of parallelism of phenotype to genotype is unexplained in these disorders. Perhaps diverse mutations responsible for UV sensitivity and deficient DNA repair may also produce profound failure of brain and somatic growth, progressive cachexia and premature aging, and tissue-selective neurologic deterioration by their roles in regulation of transcription and repair of endogenous oxidative DNA damage.

Consistency in the ratings of behaviors of communicatively impaired autistic and non-autistic preschool children.

Typically, children with disabilities are evaluated clinically by a number of professionals with different backgrounds whose task is to provide a diagnosis and an intervention plan. This study was carried out to describe interrater agreement for pairs of independent observers rating with different instruments the behaviors of 505 communicatively impaired autistic and nonautistic preschool children. Observers were parents, teachers, neurologists, and psychiatrists. Parents and teachers responded to behavioral questionnaires, neurologists filled out the mental status part of a standardized neurologic evaluation, and psychiatrists an observational questionnaire. All four types of observers rated sociability, language, play, attention, stereotyped, and other aberrant behaviors. Agreement between pairs of raters was significant but moderate. Owing to range restriction with smaller numbers of subjects, agreement decreased for ratings of subsamples divided according to diagnosis, cognitive level, or age. There were some differences among observers' ratings of the severity of particular categories of behaviors, with physicians generally viewing the children as more severely impaired and teachers as least impaired. Interrater agreement was not enhanced when parents and teachers rated similarly worded behavioral items. Modest interrater agreement in this study, like agreement among disparate raters of children's behaviors in other studies, suggests that observers are sensitive to different aspects of behavior and that their ratings are more likely to be complementary than unreliable.