Suggestive evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q.

PURPOSE: To characterize the clinical features and molecular genetic background in a family with various epilepsy phenotypes including febrile seizures, childhood absence epilepsy, and possible temporal lobe epilepsy. METHODS: Clinical data were collected. DNA and RNA were extracted from peripheral blood. A genome-wide microsatellite marker scan was performed and regions with a multipoint location score > or =1.5 were fine mapped. Functional candidate genes identified from databases and by comparing gene expression profiles of genes between affected and unaffected individuals were sequenced. Copy number variation was evaluated with array-based comparative genomic hybridization. RESULTS: The seizure phenotype was benign. Inheritance was consistent with an autosomal dominant model and reduced penetrance. The highest two-point LOD score of 2.8 was identified at marker D17S1606 in a 37cM interval on chromosome 17q12-q24. Loci on 5q11.2 and on 18p11-q11, showed LOD scores > or =1.5 after fine mapping. Sequencing of nine ion-channel genes and two (RPIP8 and SLC25A39) differentially expressed genes from 17q12-q24, as well as IMPA2 from 18p11-q11 did not reveal a pathogenic alteration. No clinically relevant copy number variation was identified. CONCLUSIONS: Our findings suggest complex inheritance of seizure susceptibility in the family with contribution from three loci, including a possible new locus on chromosome 17q. The underlying molecular defects remain unknown.

Botulinum toxin type A injections into the calf muscles for treatment of spastic equinus in cerebral palsy: a randomized trial comparing single and multiple injection sites.

OBJECTIVE: To investigate the hypothesis that the multiple-site injection technique is associated with better outcomes than the single-point injection method in children with cerebral palsy and spastic equinus gait. DESIGN: A total of 17 children (nine boys, eight girls ages 1.8-9.4 yrs; eight hemiplegics, eight diplegics, one quadriplegic; levels I-IV with the Gross Motor Function Classification System) with 25 treated lower limbs were randomized into two groups: a single-point group receiving a standard dose of botulinum toxin A injection into one site and a multiple-points group into two sites on both heads of the gastrocnemius. Active and passive range of movement, selective dorsiflexion, dynamic muscle length (modified Tardieu scale), calf tone (modified Ashworth scale), attainment of anticipated gait pattern (Goal Attainment Scale), and video gait analysis (Observational Gait Scale [OGS]) were assessed before and 1, 2, and 4 mos after intervention. RESULTS: Both groups improved in dynamic muscle length, muscle tone, OGS-total scores and initial foot contact scores and a similar number of children attained their goals on the Goal Attainment Scale. The only significant difference between the groups was observed at 2 mos in passive dorsiflexion with the knee flexed, favoring the single-point group. Though not significantly, the incidence of adverse effects was higher in the multiple-points group. CONCLUSIONS: Using the methods described, no major changes in main outcome measures were associated with the number of injection sites. Issues other than efficacy guide the decision on whether to inject in single or multiple sites when treating spastic equinus with botulinum toxin.

Upper limb function after botulinum toxin A treatment in cerebral palsy: two years follow-up of six cases.

The objective of this study was to investigate the effects of botulinum toxin A (BTXA) treatment on impairment and function of the upper limb during a 2-year follow-up period. A prospective longitudinal study design with assessments before and after intervention was utilized, involving six patients with cerebral palsy (three boys and three girls) aged 3 years 4 months to 11 years 11 months at commencement of study. The outcome measures were spasticity (modified Ashworth, MAS), active and passive range of movement (ROM), grips (pinch, key grip, 3-finger grip, narrow cylinder grip, wide cylinder grip, pen grip and diagonal grip; grasping, releasing; pronation-supination), bimanual functions, fine motor functions (Melbourne Assessment of Unilateral Upper Limb Function), movement pattern (Upper Limb Physician's Rating Scale, ULPRS), functional skills and self-care capability (Paediatric Evaluation of Disability Inventory, PEDI), upper extremity use (House Classification) and cosmetic appearance. The assessments were repeated by the same examiners at baseline and at 1, 3 and 6 months after each BTXA treatment and then every 6 months until 24 months. One subject received a total of four injections (at 0, 6, 12 and 18 months), one two injections (at 0 and 12 months) and four one injection at the beginning of the study period. Upper extremity surgery was performed on two subjects during the study and one was operated on 2 months after completion of the study. All children benefited from the BTXA treatment in terms of reduction in muscle tone and increase in active and passive ROM. By 6 months, spasticity returned, but in four children passive and especially active ROM remained better than at baseline. No significant changes in grips, bimanual tasks or Melbourne Assessment scores were detected. The change in movement pattern (ULPRS) was maintained for 3 months in two children and beyond this in four, thus extending beyond the pharmacologic effects of botulinum toxin A. All but one child showed improvement in PEDI functional skill and caregiver assistance scale scores during the 2-year period. The House classification showed a one-grade improvement in one child at 1 month and in one child at 3 months and a three-grade improvement in one child at 3 months after BTXA treatment. After each treatment, the parents reported at least a one-grade improvement in cosmetic appearance in all children at 1 month and in four children maintained at least until 6 months. In two subjects operated during the study period, a distinct improvement in active and passive ROM and a two-grade improvement in the House classification were observed after the operation. In this limited series, the reduction in muscle tone after BTXA treatment did not translate into better gripping or quality of fine motor functions (Melbourne Assessment) of the affected hand, but seemed to have a positive effect on upper limb movement pattern (ULPRS), upper extremity use (House Classification) and cosmetic appearance. Assessment of upper limb function in a child with cerebral palsy demands a variety of measures.

Low- and high-dose botulinum toxin A treatment: a retrospective analysis.

Upper limb botulinum toxin A doses in children are empirical, determined by the size of the muscle, seeking to avoid excessive weakness and deterioration of function. This study reports the effects and side effects of botulinum toxin treatment on upper limb impairment and function in 18 children with spastic or dystonic hyperactivity. A total of 54 treatments were divided into low-dose or high-dose groups according to the dose used for the target muscles. The outcome measurements included modified Ashworth Scale, passive range of movement, various grips, bimanual functions, movement pattern, House classification of upper extremity use, and subjective ratings of function and cosmetic appearance. In the functional goal group, children benefited in terms of reduction in muscle tone at elbow and wrist, and increase in passive wrist extension and House classification scores. A significant difference between the groups was observed in the House classification, favoring the low-dose group. In the nonfunctional goal group, a significant difference was detected in subjective parental cosmetic ratings, favoring the high dosage. Side effects were few and occurred mostly in the high-dose group. In conclusion, the use of higher doses in the spastic upper limb does not necessarily yield superior results compared with lower doses but increases the incidence of side effects.

Botulinum toxin treatment of spastic equinus in cerebral palsy: a randomized trial comparing two injection sites.

OBJECTIVE: To explore the clinical relevance of injection site by comparing two different injection techniques in children with cerebral palsy who have spastic equinus gait. DESIGN: A total of 19 children (13 boys, 6 girls; range, 1 yr 6 mos to 7 yrs; nine hemiplegics, eight diplegics, two quadriplegics; levels I to IV with the Gross Motor Function Classification System) participated in the study. The children were randomized into two groups: the proximal group received a botulinum toxin A injection into the proximal part of both heads of the gastrocnemius, and the distal group received a botulinum toxin A injection into the mid-belly of the muscle bulks. A single-point injection of BOTOX, 3 units/kg per site, was used. Assessments of active and passive range of motion, dynamic muscle length (modified Tardieu scale), calf tone (modified Ashworth scale), and video gait analysis (Observational Gait Scale) were performed before treatment and 3, 8, and 16 wks posttreatment. RESULTS: Active and passive dorsiflexion and calf tone in both groups and Observational Gait Scale total scores in the distal group improved at all time points. The median change from baseline values in Observational Gait Scale initial foot contact and total scores at 8 wks showed a significant difference favoring the distal group, but the clinical relevance remained tenuous. CONCLUSIONS: Using the methods described, no major changes in main outcome measures were associated with changing the injection site.

Outcome after prolonged convulsive seizures in 186 children: low morbidity, no mortality.

Prolonged convulsive seizures are a common neurological emergency and a potential cause of neuronal damage and functional sequelae. We explored the role of seizure duration and various background factors for neurological sequelae in children with prolonged convulsive seizures. The population-base of this study was all children (age < 16 years) who had been admitted to the Tampere University Hospital, Finland between 1993 and 1999 with convulsive seizures lasting more than 5 minutes. Patients were followed up individually (mean length of follow-up 2 years 1 month, range 0 to 7 years 8 months). All available data on the prolonged seizure episodes and clinical follow-up were analyzed retrospectively by a detailed review of all medical charts and records. In 186 children (94 males, 92 females; mean age 4 years 5 months, SD 3 years 10 months, range 1 month to 15 years 4 months) there were 279 separate convulsive seizure episodes lasting over 5 minutes, yielding an annual incidence of 47.5 out of every 100000 episodes. Seizure aetiology was idiopathic in 26.2% of episodes, febrile in 41.9%, remote symptomatic in 28%, and acute symptomatic in 3.9% of episodes. Mean duration of all seizure episodes was 42.5 minutes (SD 46.1 minutes) and was significantly correlated with the aetiology: shortest in the febrile group (mean 35.4 minutes) and longest in the acute symptomatic group (mean 88.6 minutes; p < 0.001). There was no mortality related directly to these acute seizure episodes. The most common sequela was an onset of epilepsy in 40 children (22%). Permanent neurological sequelae were noted in only four patients (2.2%; mean seizure duration 16 minutes) and non-permanent sequelae in six patients (3.2%; mean seizure duration 38 minutes). Neurological sequelae of prolonged convulsive seizures in children are rare and are related to aetiological factors rather than the duration of a single seizure. The role of acute seizures in the evolution of epilepsy in children remains obscure.

Visual agnosia in a child with non-lesional occipito-temporal CSWS.

In this paper we describe a case of severe visual agnosia in a child with an electrophysiological pattern of continuous spike-wave discharges in slow sleep (CSWS) in the occipito-temporal regions. The neuropsychological spectrum related to this phenomenon is discussed. Published paediatric reports associate visual agnosia (i.e. an inability to recognize objects without impairment of visual acuity) mainly with symptomatic occipito-temporal aetiology (e.g. cortical dysplasia, vascular insults) and other neurological symptoms (e.g. autism). We describe a detailed 2 year electrophysiological and neuropsychological follow-up of an 8-year-old boy with sporadic seizures, occipito-temporal CSWS and visual agnosia. The growth and neurological development of the child had been considered as normal, neurological examination did not reveal any focal signs, visual acuity was intact and MRI was normal. First EEG and six consecutive 24 h video EEG recordings during the follow-up of 22 months showed continuous spike-and-wave activity covering over 85% of the non-REM sleep. According to structured neuropsychological tests (Wechsler Intelligence Scale for Children--Third Edition, A Developmental Neuropsychological Assessment (NEPSY), Test of Visual-Perceptual Skills, Corsi block, Hooper Visual Organization Test) the boy had normal verbal intelligence but major deficits in visual perception, especially in object recognition, impaired shape discrimination and detection, and poor copying skills. Attention and executive functions were intact. There were no difficulties in short- or long-term memory. Verbal cues and naming the objects improved visual memory. Tracing the objects with a finger or by moving the head improved object recognition. Currently the boy attends a special school with a rehabilitation plan including neuropsychological and occupational therapies. This case adds a new facet to the spectrum of neuropsychological deficits in children with CSWS. Sleep EEG should be included in the etiological studies of children with specific neuropsychological problems and detailed neuropsychological assessment is needed for diagnostic and rehabilitation purposes.

Idiopathic generalised epilepsies with 3 Hz and faster spike wave discharges: a population-based study with evaluation and long-term follow-up in 71 patients.

For several years we have been following patients with intractable, childhood-onset idiopathic generalised epilepsies with > or = 3 Hz spike-wave discharges. Our need to find explanations for their intractability was the starting point for this study. We were interested in identifying characteristics, which would predict intractability; evaluating how these patients were treated and whether polytherapy was useful. We identified patients with > or = 3 Hz spike-wave discharges by reviewing EEG reports recorded between 1983 and 1992. Data were collected from medical records and through personal interviews. We identified 82 patients with tentative idiopathic generalised epilepsy. Eleven were excluded. Thirty-eight patients had childhood absence epilepsy, 18 had juvenile absence epilepsy, 13 had juvenile myoclonic epilepsy and two had eyelid myoclonia with absences: 89.5, 78, 38 and 0% of the patients in each group, respectively, had been seizure free for more than 2 years. Twenty percent of the patients had intractable seizures. All intractable patients with juvenile absence epilepsy had rhythmic, random eyelid blinking and generalised tonic-clonic seizures. A history of more than ten generalised tonic-clonic seizures was associated with intractability in juvenile myoclonic patients. Monotherapy with ethosuximide or valproate resulted in seizure control in 65% of patients. Seventeen patients (24%) were treated with polytherapy, six achieved remission. These six patients had childhood absence epilepsy and juvenile absence epilepsy. Positive outcome was found in childhood absence epilepsy and juvenile absence epilepsy. Intractable seizures were more frequent among patients with juvenile myoclonic epilepsy. None of them benefited from polytherapy with conventional anti-epileptic drugs.