Disorders of early language development in Dravet syndrome.

The aim of this study was to investigate language disorders prospectively in patients with Dravet syndrome (DS) during the first years of life in order to identify their features and possibly the underlying mechanisms of the disease. At the Child Neurology Unit of Catholic University in Rome (Italy), thirteen patients with typical findings of DS were enrolled in the study. Full clinical observations, including neurological examination and long-term EEG monitoring, were prospectively and serially performed until a mean of 6years of age (range: 4years to 7years and 8months). The epileptic history was also collected in each case. In particular, developmental, cognitive, and detailed language assessments were performed with different tests according to the age of the patient. In addition to cognitive decline, characteristic language impairment was also found with a relative preservation of receptive abilities (comprehension) and a strong impairment of productive skills. This defect in sensorimotor verbal processing integration is discussed to highlight the possible mechanisms underlying cognitive decline.

Posterior resection for childhood lesional epilepsy: neuropsychological evolution.

The aim of this study was to provide information on the neuropsychological evolution of children with symptomatic epilepsy who have undergone surgical resection of posterior (occipitoparietal) lesions. Twelve children with epilepsy with parietal and/or occipital lesions were enrolled in the study and followed after surgical resection: full clinical and epileptic examinations were performed before and after surgery, as was a neuropsychological study of both general and specific cognitive abilities. Epilepsy evolution was generally good (Engel classification IA in nine cases) with persistent selective neurological impairments (eye field defects, sensory unilateral spatial neglect) in some cases, consistent with the lesion site. Neuropsychological defects before surgery in the absence of refractory epilepsy were minimal with a normal global cognitive competence; yet, the relatively low performance scores with some impairment of specific cognitive skills were strictly correlated with defects in visual perceptive skills in both right- and left-sided lesions. Surgery seems to have improved performance abilities, whereas other abnormal specific skills did not change with the exception of working memory that in some cases was defective before surgery and normalized after lesion removal. Our study in this particular cohort of children with epileptogenic occipitoparietal lesions thus confirmed a trend toward a benign epileptic and neurodevelopmental outcome after surgical resection of the lesion.

Cognitive and behavioral characteristics of children with Dravet syndrome: an overview.

We report an overview on early development of children with Dravet syndrome. After a historical outline of literature data, we refer to an Italian multicentric project, partially still in course. Because in the first year of life development seems impaired in Dravet syndrome as studies on precognitive abilities would show, defects in early development of visual function were detected heralding the subsequent cognitive decline. The delay of cognitive development, due to stagnation rather than a real deterioration, begins after the second year of life, although the age of onset varies. The extreme variability of development phenotype is confirmed and widened including also cognitive decline and severity of different defects of neuropsychological abilities as well as behavioral problems, especially associated with the cognitive decline. Mechanisms underlying neurodevelopment disorders and possible role of genetics are discussed.

Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients.

PURPOSE: To clarify the role of epilepsy and genetic background in determining the cognitive outcome of patients with Dravet syndrome. METHODS: In this retrospective study, we reviewed the clinical history and cognitive development of 26 patients who had been followed with standardized evaluations since seizure onset. The cognitive outcome was quantified as differential general quotient (dGQ) between ages 12 and 60 months. Statistical analysis correlated the dGQ with genotype and epilepsy course. KEY FINDINGS: Epilepsy started at the mean age of 5.6 months. All patients experienced prolonged convulsive seizures, whereas absences and myoclonus were reported in 17. Cognitive outcome was poor in almost all patients; the mean dGQ was 33 points, varying from 6-77 points. The analysis of individual cognitive profiles identified seven patients in whom the dGQ was <20 points; the main clinical characteristic in this subset of patients was lack of early absences and myoclonus. The statistical analysis of the whole series failed to reveal significant differences in cognitive outcome with regard to the presence of SCN1A mutations and their type. In particular, mutation-carrier patients with the best cognitive outcome harbored either missense or truncating mutations. SIGNIFICANCE: Dravet syndrome encompasses different epileptic and cognitive phenotypes that probably result from both genetic and epigenetic factors. In this series, early appearance of myoclonus and absences was associated with the worst cognitive outcome.

Auditory processing in infancy: do early abnormalities predict disorders of language and cognitive development?

Increasing attention has been devoted to the maturation of sensory processing in the first year of life. While the development of cortical visual function has been thoroughly studied, much less information is available on auditory processing and its early disorders. The aim of this paper is to provide an overview of the assessment techniques for early auditory processing. While otoacoustic emissions and auditory brainstem responses are well-established tools for neonatal screening of hearing loss, there have been less consistent results for neurophysiological assessments of central auditory processing in clinical practice. Early auditory event-related potentials could provide valuable diagnostic information, but their use as a possible clinical screening method is still limited and should be further assessed. Behavioural tests are few and are greatly needed in young infants as they could provide a more easily used tool for detecting the preconditions of early cerebral auditory impairment.

Multicenter prospective longitudinal study in 34 patients with Dravet syndrome: Neuropsychological development in the first six years of life.

The objective of this study was to identify developmental trajectories of developmental/behavioral phenotypes and possibly their relationship to epilepsy and genotype by analyzing developmental and behavioral features collected prospectively and longitudinally in a cohort of patients with Dravet syndrome (DS). Thirty-four patients from seven Italian tertiary pediatric neurology centers were enrolled in the study. All patients were examined for the SCN1A gene mutation and prospectively assessed from the first years of life with repeated full clinical observations including neurological and developmental examinations. Subjects were found to follow three neurodevelopmental trajectories. In the first group (16 patients), an initial and usually mild decline was observed between the second and the third year of life, specifically concerning visuomotor abilities, later progressing towards global involvement of all abilities. The second group (12 patients) showed an earlier onset of global developmental impairment, progressing towards a generally worse outcome. The third group of only two patients ended up with a normal neurodevelopmental quotient, but with behavioral and linguistic problems. The remaining four patients were not classifiable due to a lack of critical assessments just before developmental decline. The neurodevelopmental trajectories described in this study suggest a differential contribution of neurobiological and genetic factors. The profile of the first group, which included the largest fraction of patients, suggests that in the initial phase of the disease, visuomotor defects might play a major role in determining developmental decline. Early diagnosis of milder cases with initial visuomotor impairment may therefore provide new tools for a more accurate habilitation strategy.

Visual and visuoperceptual function in children with Panayiotopoulos syndrome.

PURPOSE: The aim of this study was to assess behavioral aspects of visual function and visuoperceptual abilities in patients with Panayiotopoulos syndrome (PS), and their possible associations with clinical and electroencephalography (EEG) findings in order to establish the possible effect of interictal paroxysmal activity on visual performance. METHODS: The cohort included 28 patients (14 male and 14 female) of ages ranging between 4 and 15 years. All patients underwent serial videopolygraphic studies and a detailed battery of tests assessing visual abilities, including assessment of acuity, stereopsis, visual fields, and visuoperceptual abilities; tests included the Movement Assessment Battery for Children, the Visuo Motor Integration tests, and evaluation of motion and form coherence threshold. RESULTS: On the assessment of visual function, only 4 of the 28 (15%) had abnormal crowding acuity and one had abnormal stereopsis. On the visuoperceptual assessment, one patient had abnormal results on the Visuo Motor Integration tests, and one on the Movement Assessment Battery for Children, whereas 4 (15%) had abnormal results for form coherence threshold and one for motion threshold. DISCUSSION: Our results suggest that, although most of our patients had focal or diffuse EEG abnormalities involving the occipital regions, abnormalities of visual and visuoperceptual function were relatively uncommon. Age at onset of seizure <5 years and EEG activation to eye closure and during sleep can be considered as factors that slightly increased the risk for developing visual abnormalities. Their presence, however, was not always associated with abnormal visual findings.

Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case.

The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1-26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.

Italian consensus conference on epilepsy and pregnancy, labor and puerperium.

To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15-16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.

Neurodevelopmental evolution of West syndrome: a 2-year prospective study.

OBJECTIVE: The aim of this study was to evaluate the epileptic and developmental evolution in infants with West syndrome. METHODS: A prospective study of 21 infants was performed, with a follow-up at 2 years. Serial assessment included long-term EEG monitoring, visual and auditory evaluation and assessment of neurodevelopment. RESULTS: Neurosensory and developmental impairments at the spasm onset were transitory in seven cases, including four cryptogenic forms. In all other cases, there was a progressive worsening in neurosensory and developmental impairments. The epileptic evolution was generally better: in 11 of the 16 infants without seizures at outcome, spasms had already disappeared by 2 months after disease onset. Statistic analysis of results showed a correlation between neurosensory impairment and development throughout the whole follow-up. In addition, visual function at T1 resulted significant predictor of developmental outcome. Among the epileptic features, disorganization of slow sleep was an unfavorable prognostic factor. CONCLUSION: Some forms of West syndrome are confirmed to have a benign evolution: among them there are not only cryptogenic cases but also symptomatic ones without significant neurodevelopmental impairment. Abnormalities of sleep organization, expression of the pervasive epileptic disorder, seem to play a role in determining a developmental deterioration. Neurosensory impairment since the onset of the disease could be a relevant cause of the developmental disorder.

Visual development in infants with prenatal post-haemorrhagic ventricular dilatation.

OBJECTIVE: The aim of this study was to assess visual function in 13 infants with evidence of prenatal post haemorrhagic ventricular dilatation. DESIGN: Infants were assessed at 5, 12 and 24 months using a battery of tests specifically designed to assess various aspects of visual function in infancy. Visual findings were correlated with several variables, including extent of the lesion and presence of epilepsy. RESULTS AND CONCLUSIONS: Abnormalities of visual function were frequent (over 60%) in our cohort at age 2 years, ranging from isolated abnormal ocular movements to severe abnormalities of all the aspects of visual function assessed. The most severe and persistent abnormalities of visual function were found in infants with grade IV intraventricular haemorrhage and shunted hydrocephalus who also had epilepsy in the first year.

Thalamic atrophy in infants with PVL and cerebral visual impairment.

The aim of this retrospective study was to establish the presence and severity of cerebral visual impairment in preterm infants with PVL. We also wished to establish whether abnormalities of visual function are related to brain MRI findings and more specifically not only to the involvement of optic radiations and occipital cortex but also to changes in the thalami, that are often affected in infants with PVL. Twelve infants with cystic PVL were assessed at 1 year (+2) corrected age with a battery of tests specifically designed to assess various aspects of visual function in infancy, such as ocular movements, visual acuity, visual fields and fixation shift. All infants also had a brain MRI. Eleven of the 12 had involvement of the optic radiations: all had some abnormalities of visual function and visual impairment was more severe in infants with more extensive involvement of the optic radiations. The child with normal optic radiations had normal visual function. Six of the 12 infants also had obvious signs of atrophy of the thalami and all had severe and wide-ranging abnormalities of visual function in all testing domains. Two children had equivocal atrophy of the thalami, both had some abnormalities of visual function. Four children had normal thalami and had normal visual function or only minor abnormalities on one of the visual tests. Our results suggest that the atrophy of the thalami may play an additional role in the abnormal development of visual function in infants with PVL and abnormal optic radiations.

Outlining a core neuropsychological phenotype for Dravet syndrome.

An up-to-date review on neuropsychological phenotypes in Dravet syndrome is reported. After recalling the results of various though not numerous studies in the literature, primarily retrospectively, the hypothesis of an original neuropsychological phenotype in Dravet syndrome is presented, consisting of a defect in sensorimotor integration, especially of visuoconstructive abilities. That is particularly evident in the less impaired patients and in the first several years of life. This core phenotype is eventually considered inside the analysis of the etiological multifactorial origin of the cognitive decline, which is especially expressed by the encephalopathy/channelopathy controversy.

Cognitive-behavioral profiles in teenagers with Dravet syndrome.

AIM: To investigate behavior and cognitive performances of teenage patients with Dravet syndrome (DS). METHODS: We enrolled 20 teenage patients (12 females and 8 males) with DS, followed in the Child Neurology Unit of the Catholic University (Rome). Patients underwent a full clinical examination including behavioral and cognitive assessments (respectively, CBCL and Wechsler scales). RESULTS: All patients showed behavior disorders and mental retardation, mild in six cases, moderate in seven and severe in the remaining seven. Among mildly retarded patients visual function, particularly visuo-motor abilities resulted mostly impaired in Wechsler subtests, whereas verbal skills were relatively preserved. In contrast, a general cognitive impairment was observed in moderately and severely retarded patients. CONCLUSIONS: Our teenage patients with DS compared with other series at different ages (young childhood, adulthood) suggest a progressivity of neurological and neuropsychological signs. A visuomotor default and a relative preservation of verbal skills, like what has been found in previous reports of younger patients, are still evident in mildly impaired cases. Therefore, the progression over time of these cases toward a generalized impairment may be suggested, but only longitudinal studies can confirm it. There was a possible responsibility of some epileptic disorders in worsening the neuropsychological outcome (early myoclonic seizures and atypical absences, as well as persistent EEG background slowness in the last 3years).

Epilepsy in shunted posthemorrhagic infantile hydrocephalus owing to pre- or perinatal intra- or periventricular hemorrhage.

Epilepsy is relatively common in infants with hydrocephalus. Its mechanism is controversial; in fact, studies on etiologically heterogeneous series are not able to clarify the mechanism generating epilepsy or to suggest effective prevention and treatment strategies. Our study is aimed at assessing the onset and evolution of epilepsy, as well as concurrent cognitive development of a homogeneous series of shunted posthemorrhagic hydrocephalus owing to pre- or perinatal intra- or periventricular hemorrhage. Forty patients were enrolled in the study. Twenty-six were patients with grade II-III intraventricular hemorrhage, 16 of whom had associated ischemic lesions. In the remaining 14 patients, a grade IV intra-ventricular hemorrhage was found. Epilepsy was observed in 27 patients. Aside from 10 cases with nonsyndromic forms of epilepsy, it was possible to define at least three different age-dependent epileptic syndromes: symptomatic neonatal location-related epilepsy with transient West's syndrome in infancy in 5 patients; West's syndrome in 8 patients; and continuous spike-waves during sleep in 4 patients. Epilepsy was significantly correlated with ischemic lesions only. Early thalamic injuries frequently evolved toward continuous spike-waves during sleep, indicating that patients with thalamic injury must be monitored to detect continuous spike-waves during sleep early. Cerebellar atrophy, in addition to epilepsy and other brain injuries, accounted for disorders of cognitive development.

Sleep-potentiated epileptiform activity in early thalamic injuries: Study in a large series (60 cases).

OBJECTIVE: The study aims at a better definition of continuous spike-waves during sleep (CSWS) with an early thalamic lesion, focusing on various grades of sleep-potentiated epileptiform activity (SPEA). Their possible relationship with different clinical features was studied to try to define prognostic factors of the epileptic disorder, especially relating to behavior/cognitive outcome, in order to improve prevention and treatment strategies. METHODS: Sixty patients with early thalamic injury were followed since the first registration of SPEA with serial neurological, long term EEG monitoring and neuropsychological examinations, as well as neuroimaging and a detailed clinical history. They were classified in three different groups according to the sleep spike-waves (SW) quantification: electrical status epilepticus during sleep (ESES), more than 85% of slow sleep; overactivation between 50% and 85% and simple activation between 10 and 50%). Results were then examined also with a statistical analysis. RESULTS: In our series of CSWS occurring in early brain injured children with unilateral thalamic involvement there is a common neuropathologic origin but with various grades of SPEA severity. Statistical analysis showed that patients evolving toward ESES presented more commonly the involvement of the mediodorsal part of thalamus nuclei and a bilateral cortico-subcortical brain injury, epilepsy was more severe with a delayed onset; moreover, in the acute stage .ESES patients presented the worst behavior/cognitive performances. As to cognitive and behavior outcome, longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase appear linked to a poor outcome; some particular neuropathology (ischemic stroke and haemorrhagic infarction) as well as hydrocephalus shunting are associated with behavior disorders. CONCLUSIONS: Discrete features seem to support different underlying mechanisms in ESES patients in comparison with less severe SPEA; they represent negative prognostic factors. Longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase seem predictive of a worse cognitive/behavior outcome.

Behavioral assessment of language brain processing in the first year of life.

An up-to-date review of the behavioral assessments of language development in the first year of life is reported. After recalling the anatomical bases of the early development of the auditory system, the different stages of language development during the first year of life are considered: discrimination, transition and perception. The different kinds of behavioral assessment during the course of the first year are then described by stressing their indications and limitations.

Cognitive decline in Dravet syndrome: is there a cerebellar role?

PURPOSE: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern. METHODS: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills. RESULTS: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders. CUNCLUSIONS: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies.

Early development in Dravet syndrome; visual function impairment precedes cognitive decline.

Aim of the study was to describe prospectively the early neuropsychological evolution including the first pre-cognitive stages of the Severe Myoclonic Epilepsy in Infancy (SMEI) or Dravet syndrome. Five cases, four of whom since before a diagnostic evidence of the Dravet syndrome, were followed up. Full clinical assessment including developmental, visual function and behaviour assessments were serially performed. In four cases, a variable onset age of cognitive decline assessed with developmental scales was preceded some months before by an impairment of visual function; the remaining patient during all the course of follow-up till 51 months of age showed a normal development without visual impairment. A cognitive decline with variable onset was generally confirmed in Dravet syndrome. The previous early impairment of visual function seems to herald the cognitive decline and provides useful prognostic information; furthermore, it possibly suggests some clues for a better understanding of the mechanisms of cognitive deterioration in this syndrome.

Neuropsychological development in children with Dravet syndrome.

PURPOSE: Aim of this study is to report a detailed profile of neuropsychological development in children with Dravet syndrome. METHODS: Twelve children with Dravet syndrome were longitudinally assessed using a detailed clinical and neuropsychological evaluation. Six had typical features of severe myoclonic epilepsy in infancy (SMEI) whereas the other six resulted borderline. All twelve underwent serial neuropsychological assessments with neurodevelopmental scales and further assessment of specific cognitive abilities. RESULTS: Our results reported an apparent normal development before disease onset, a general evolution in two main stages, more active the first one and with a general trend towards a clinical stabilization afterwards. The onset of cognitive decline was generally later than what is reported in other series; furthermore, the impairment of cognitive development is less severe, especially in borderline cases. As to specific cognitive competence, attention, visual motor integration, visual perception as well as executive functions are the most impaired abilities; language appears less involved, with a predominance of phonological defects. CONCLUSIONS: In our cohort the global development of patients appear less affected than in previous studies. Furthermore, our study points out an impairment of several specific cognitive skills even in patients with a developmental quotient apparently in the normal range. Language and other cognitive skill impairment such as attention, visuo-spatial organization, working memory and executive function appear consistent with what is usually found in cerebellar disorders.