Evaluation of the Effects of Clobazam on Seizure Control and Quality of Life in Children With Lennox-Gastaut Syndrome: A Pilot Study.

PURPOSE: This is a prospective study of children with Lennox-Gastaut syndrome receiving clobazam as adjunctive therapy. This pilot study aims to examine medication effectiveness as it relates to seizure reduction, as well as improvement in parent-reported behavior and quality of life (QOL). METHODS: Ten patients with Lennox-Gastaut syndrome aged 3-11 years were enrolled in this 6-week, 4 phase study. Seizure frequency, QOL, and Aberrant Behavior Checklist questionnaires were evaluated at 0, 2, 6, and 10 weeks during the study. RESULTS: Patients showed improvement on indices of QOL, including physical activities (62.5%), well-being (37.5%), cognition (87.5%), social activities (37.5%), behavior (87.5%), general health (50%), and overall QOL (87.5%). The Quality of Life in Childhood Epilepsy (QOLCE) questionnaire revealed significant improvement in cognition (P = .008), social activities (P = .049), behavior (P = .038), and overall QOL (P = .018). The Aberrant Behavior Checklist exhibited a trend toward improvement in hyperactivity. CONCLUSION: There was improvement in all patients with documented baseline seizures (8/10), with 5 showing significant improvement (95%-100% reduction) and 3 showing minor improvement (7%-23% reduction). Statistically significant improvement in areas of cognition, social activities, behavior, and overall QOL were seen. An overall trend toward a positive well-being was seen in our patients with clobazam, as adjunct therapy for Lennox-Gastaut syndrome in children.

Cognitive Functioning in Patients with Pediatric-Onset Multiple Sclerosis, an Updated Review and Future Focus.

Pediatric-onset multiple sclerosis (POMS) is relatively rare, but as technology and neuroimaging advance, an increasing number of cases are identified, and our understanding of how multiple sclerosis (MS) impacts the developing brain improves. There are consistent findings in the literature highlighting the impact of MS and other demyelinating diseases on cognitive functioning and cognitive development. We also have a better understanding of how POMS impacts psychosocial functioning and functional outcomes in daily living. This paper hopes to review findings associated with cognitive and psychosocial functioning in patients with POMS, as well as explore more recent advances in the field and how they relate to cognitive and psychosocial outcomes. We also discuss the ongoing need for future studies with a focus on better understanding deficits and disease correlates, but also preventative measures and potential rehabilitation.

Long-Term Neurocognitive, Psychosocial, and Magnetic Resonance Imaging Outcomes in Pediatric-Onset Acute Disseminated Encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder that is usually self-limited. Recent studies have suggested ongoing neurological deficits and neurocognitive impairment in these patients. Little information on the correlation of clinical and neuroimaging markers in ADEM is available. We examined potential clinical factors (e.g., age of onset, acute symptom duration, magnetic resonance imaging [MRI] lesions) and their relation to neurocognitive and psychosocial outcomes. METHODS: This is a retrospective chart review of consecutive pediatric patients diagnosed with ADEM between 2006 and 2012. Patients were evaluated with standard neurological assessment, MRI of the brain, and neuropsychological evaluation. RESULTS: Twenty-three patients with ADEM with average age at neuropsychological assessment of 10.1 years (±3.50) were included. Five (22.7%) patients were impaired on three or more neurocognitive measures. Psychosocial problems were reported in 20%-40% of patients. Earlier age of onset was correlated with poorer sustained attention and psychosocial problems, whereas acute symptom duration and Expanded Disability Status Scale were not. MRI outcomes were correlated with psychosocial outcomes but not neuropsychological findings. CONCLUSIONS: Our findings suggest lingering cognitive and psychosocial deficits in children with a history of ADEM. Clinical features and MRI findings correlated more strongly with psychosocial outcomes than cognitive functioning. Further studies are needed to confirm relationships and other possible contributing factors to lingering deficits.

Cognitive deficits in pediatric-onset multiple sclerosis: what does the future hold?

Pediatric-onset multiple sclerosis is relatively rare and research regarding disease characteristics is in its infancy. Regardless, there are a growing number of studies finding early cognitive deficits in this population. There are some similarities in outcomes to those seen in the adult-onset multiple sclerosis population, but also several important differences. With specific regard to cognitive functioning in pediatric-onset multiple sclerosis, there is evidence of deficit in nearly a third of patients, with impairment primarily in areas of processing speed, visual-spatial processing and language. There are additional findings of fatigue and depression that impact functional outcomes requiring further attention in assessment and treatment considerations. This paper also explores other areas requiring increased focus, including treatment and outcomes, neuroimaging and additional disease-modifying factors (comorbidities, socioeconomic status, race and so on).

Fatigue and depression in children with demyelinating disorders.

Fatigue and depression have been shown to be significant problems in children with multiple sclerosis. The rate at which these conditions occur in children with other acquired demyelinating syndromes is unknown. In this cross-sectional study, the authors evaluated 49 children with demyelinating disorders (multiple sclerosis and acute disseminated encephalomyelitis) and 92 healthy controls for depression and/or fatigue using the Behavior Assessment System for Children, Second Edition behavior and mood rating scale and Varni PedsQL Multidimensional Fatigue Scale. The parents of acquired demyelinating syndrome patients were more likely to report elevated depressive symptoms (30.8% vs 10.8%, P = .008). Elevated parent and self-reported total fatigue (25% vs 0%, P < .001, 26.7% vs 8.6%, P = .024) was seen in the patient cohort. The authors conclude that fatigue and depression are far more common in children with acquired demyelinating syndromes than in controls. Clinical attention to and implementation of effective therapies oriented toward these conditions in children with acquired demyelinating syndromes is needed.

Cognitive impairment occurs in children and adolescents with multiple sclerosis: results from a United States network.

In the largest sample studied to date, we measured cognitive functioning in children and adolescents with pediatric multiple sclerosis (n = 187) as well as those with clinically isolated syndrome (n = 44). Participants were consecutively enrolled from six United States Pediatric Multiple Sclerosis Centers of Excellence. Participants had a mean of 14.8 ± 2.6 years of age and an average disease duration of 1.9 ± 2.2 years. A total of 65 (35%) children with multiple sclerosis and 8 (18%) with clinically isolated syndrome met criteria for cognitive impairment. The most frequent areas involved were fine motor coordination (54%), visuomotor integration (50%), and speeded information processing (35%). A diagnosis of multiple sclerosis (odds ratio = 3.60, confidence interval = 1.07, 12.36, P = .04) and overall neurologic disability (odds ratio = 1.47, confidence interval = 1.10, 2.10, P = .03) were the only independent predictors of cognitive impairment. Cognitive impairment may occur early in these patients, and prompt recognition is critical for their care.

Acuted disseminated encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) is a disorder of the central nervous system (CNS) characterized by an acute event, typically with encephalopathy, in which diffuse CNS involvement occurs. It may follow an infectious event and occurs more commonly in young children. Pulse steroid treatment is frequently used to treat ADEM. Although ADEM is typically described as a benign condition, with children generally recovering motor function and resolution of lesions on magnetic resonance imaging (MRI), residual cognitive deficits may occur. This chapter aims to review the clinical features, typical presentation, differential diagnosis, treatment and prognosis of ADEM.

Disease progression in pediatric multiple sclerosis: disparities between physical and neurocognitive outcomes.

Growing information regarding the neurocognitive burden of pediatric multiple sclerosis (MS) has become available in recent years. Whereas natural history studies suggest a longer time to irreversible disability in the pediatric population with MS than in the adult MS population, increasing knowledge suggests a relatively rapid accrual of cognitive deficits in this young population. This article will explore this paradox, taking into account studies that have focused on neuroimaging, cognition and outcomes in pediatric MS.

Cerebellar mutism in pediatric acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis is a demyelinating process affecting multiple areas of the central nervous system, frequently including the cerebellum. Cerebellar insult may lead to absence of speech or cerebellar mutism. Cerebellar mutism often occurs in young children after posterior fossa tumor resection, and generally appears as part of a larger subset of neurobehavioral signs and personality changes known as posterior fossa syndrome. Information on the impact of widespread cerebellar involvement on speech production, behavior, and long-term outcomes in acute disseminated encephalomyelitis is limited. We describe cases of acute disseminated encephalomyelitis with predominantly cerebellar involvement, with specific attention to cerebellar mutism. We conducted a retrospective chart review of children diagnosed with acute disseminated encephalomyelitis between 2005-2009 at a pediatric multiple sclerosis and demyelinating disorders clinic. Of 19 patients diagnosed with acute disseminated encephalomyelitis, six (32%) manifested primary cerebellar involvement. Of these six, four (67%) exhibited acute language disturbance, with three (50%) exhibiting mutism. The three patients with cerebellar mutism experienced protracted speech and language deficits after follow-ups from 6 months to 4 years. Widespread cerebellar involvement in acute disseminated encephalomyelitis may result in cerebellar mutism, in addition to persistent neurocognitive and behavioral problems.

Thalamic atrophy and cognition in unilateral temporal lobe epilepsy.

This study examined quantitative magnetic resonance volumes of the thalamus and hippocampus and determined their relationship with cognitive function and clinical seizure characteristics in a sample of 46 unilateral temporal lobe epilepsy (TLE) subjects (20 left and 26 right) and 29 controls. The hippocampus and thalamus exhibited different patterns of volume abnormality, different associations with clinical seizure characteristics, and different patterns of relationship with cognitive measures. Hippocampal volume reduction was primarily ipsilateral to the seizure focus, and thalamic volume reduction was bilateral. Ipsilateral hippocampal volume was significantly correlated with both early neurodevelopmental features (age of seizure onset) and disease characteristics (duration of epilepsy), whereas thalamus integrity was related only to disease variables. Hippocampal volume showed a selective association with verbal memory performance. In contrast, both left and right thalamic volumes were significantly correlated with performance on both memory and nonmemory cognitive domains. These findings underscore the importance of thalamic atrophy in chronic TLE and its potential implications for cognition.

MRI volume loss of subcortical structures in unilateral temporal lobe epilepsy.

Few studies have examined the relative degree of brain volume loss in both the hippocampi and subcortical structures in unilateral temporal lobe epilepsy (TLE) and their association with clinical seizure correlates. In this study, quantitative MRI volumes were measured in the hippocampus, thalamus, caudate, putamen, and corpus callosum in 48 patients with unilateral TLE (26 right, and 22 left) and compared with the volumes of 29 healthy controls. The ipsilateral hippocampus, corpus callosum, and bilateral thalami exhibited the greatest volume loss, reflected by large to moderate effect size differences compared with controls. Bilaterally, the putamen showed the next highest volume reduction. The contralateral hippocampus and bilateral caudate nuclei showed the least volume reduction, characterized by small effect sizes. Furthermore, clinical seizure characteristics (e.g., duration of epilepsy) exhibited different patterns of association with the volume reductions observed across these structures. Findings suggest that distinct neurodevelopmental features may play a role in the volume abnormality observed in these regions.

Executive functioning in childhood epilepsy: parent-report and cognitive assessment.

There is considerable interest in the assessment of executive function (EF) in pediatric clinical populations but only a few well-standardized measures exist. We examined EF in 53 children aged 8 to 18 years with recent onset epilepsy (31 males, 22 females) and 50 control children (23 males, 27 females) using the Behavior Rating Inventory of Executive Function (BRIEF) and the Delis-Kaplan Executive Function System (D-KEFS). Thirty children had localization-related epilepsy and 23 had idiopathic generalized epilepsy; average duration of 10 months (SD 4y 1mo) and onset age of 11 years 6 months (SD 3y 6mo). The study sample was characterized by good seizure control, with 40 participants taking one antiepileptic drug (AED), one taking two AEDs, and 12 not treated pharmacologically. Children with epilepsy showed greater executive difficulties on both measures than children in the control group. The BRIEF and D-KEFS were significantly correlated, and an 'at-risk' group identified from the BRIEF was more significantly impaired on the D-KEFS than a 'low risk' group. The BRIEF was also a better predictor of performance on the D-KEFS than the Child Behavior Checklist. These findings indicate that children with recent onset epilepsy show significant difficulties in E F, and demonstrate the utility of parent ratings (BRIEF) in the assessment of EF.

Cerebellar atrophy in temporal lobe epilepsy.

PURPOSE: The goal of this work was to determine the presence and degree of cerebellar atrophy in chronic temporal lobe epilepsy, its clinical seizure correlates, and its association with general cortical atrophy. METHODS: Study participants were 78 persons with temporal lobe epilepsy and 63 age- and gender-matched healthy controls. All subjects underwent high-resolution MRI with manual tracing of the cerebellum. Clinical seizure features and history were obtained by structured interview and review of medical records. RESULTS: The epilepsy group exhibited significant abnormality in cerebellar volume, with mean reductions ranging from 4 to 6.6% depending on adjustments. Significantly more individual subjects with epilepsy exhibited cerebellar atrophy compared with controls across all operational definitions or thresholds of abnormality including z < or = -2.0 (13% TLE, 3.4% controls) and z < or = 1.5 (22% TLE, 3.4% controls). Clinical seizure features reflecting both neurodevelopmental (history of initial precipitating injuries) and severity of course (longer duration, increased number of lifetime generalized tonic-clonic seizures) factors were associated with cerebellar atrophy. Atrophy of the cerebellum could be observed independent of more general (cerebral) atrophic processes. CONCLUSIONS: The presence of cerebellar atrophy is a reflection of the extratemporal abnormalities that can be observed in localization-related temporal lobe epilepsy, which may be due, at least in part, to factors associated with epilepsy chronicity.

Ipsilateral and contralateral MRI volumetric abnormalities in chronic unilateral temporal lobe epilepsy and their clinical correlates.

PURPOSE: To assess the presence, extent, and clinical correlates of quantitative MR volumetric abnormalities in ipsilateral and contralateral hippocampus, and temporal and extratemporal lobe regions in unilateral temporal lobe epilepsy (TLE). METHODS: In total, 34 subjects with unilateral left (n = 15) or right (n = 19) TLE were compared with 65 healthy controls. Regions of interest included the ipsilateral and contralateral hippocampus as well as temporal, frontal, parietal, and occipital lobe gray and white matter. Clinical markers of neurodevelopmental insult (initial precipitating insult, early age of recurrent seizures) and chronicity of epilepsy (epilepsy duration, estimated number of lifetime generalized seizures) were related to magnetic resonance (MR) volume abnormalities. RESULTS: Quantitative MR abnormalities extend beyond the ipsilateral hippocampus and temporal lobe with extratemporal (frontal and parietal lobe) reductions in cerebral white matter, especially ipsilateral but also contralateral to the side of seizure onset. Volumetric abnormalities in ipsilateral hippocampus and bilateral cerebral white matter are associated with factors related to both the onset and the chronicity of the patients' epilepsy. CONCLUSIONS: These cross-sectional findings support the view that volumetric abnormalities in chronic TLE are associated with a combination of neurodevelopmental and progressive effects, characterized by a prominent disruption in ipsilateral hippocampus and neural connectivity (i.e., white matter volume loss) that extends beyond the temporal lobe, affecting both ipsilateral and contralateral hemispheres.

Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test.

As many as 66% of systemic lupus erythematosus (SLE) patients have been reported to have cognitive deficits. These deficits are often associated with information processing speed and working memory. Similarly, processing speed and working memory impairments are the hallmark of cognitive dysfunction in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) places high demands on processing speed and working memory. Fisk and Archibald, however, demonstrated that the total score of the PASAT does not accurately reflect impairments in these cognitive processes. They found that MS patients used a chunking strategy to obtain correct responses and reduce the cognitive demands of the task. In the present study, PASAT performance was examined for 45 SLE patients and 27 controls using alternative scoring procedures. Although the total number of correct responses did not differ between SLE and controls at the 2.4 or 2.0 s presentation rates, SLE patients had fewer dyads (correct consecutive responses) than controls at the faster rate, and more chunking responses than controls at both rates. Disease activity, disease duration, depression, fatigue, and corticosteroids could not account for these differences. The findings suggest that SLE patients, like MS patients, chunk responses more often than controls, and that this scoring procedure may better reflect the working memory and processing speed deficits present in SLE.