Lakshmi Nagarajan

Neurological Manifestations of Enterovirus 71 Infection in Children during an Outbreak of Hand, Foot, and Mouth Disease in Western Australia

Enterovirus 71 (EV71) causes epidemics of hand, foot, and mouth disease associated with neurological complications in young children. We report an outbreak of EV71-associated neurological disease that occurred from February through September 1999 in Perth, Western Australia. Fourteen children with culture-proven, EV71-induced neurological disease were identified. Nine patients (64%) developed severe neurological disease; 4 of these patients developed long-term neurological sequelae. Neurological syndromes included aseptic meningitis, Guillain-Barré syndrome, acute transverse myelitis, acute cerebellar ataxia, opso-myoclonus syndrome, benign intracranial hypertension, and a febrile convulsion. Clinical and magnetic resonance imaging data indicated that immunopathology was a major factor in the pathogenesis of neurological disease in this outbreak. This finding is in contrast to reports of previous EV71 epidemics, in which virus-induced damage to gray matter was the most frequent cause of neurological disease.

Differences in sensory and motor cortical organization following brain injury early in life

There have been a number of physiological studies of motor recovery in hemiplegic cerebral palsy which have identified the presence of novel ipsilateral projections from the undamaged hemisphere to the affected hand. However, little is known regarding the afferent projection to sensory cortex and its relationship to the reorganized cortical motor output. We used transcranial magnetic stimulation (TMS) to investigate the corticomotor projection to the affected and unaffected hands in a group of subjects with hemiplegic cerebral palsy, and also performed functional magnetic resonance imaging (fMRI) studies of the patterns of activation in cortical motor and sensory areas following active and passive movement of the hands. Both TMS and fMRI demonstrated a normal contralateral motor and sensory projection between the unaffected hand and the cerebral hemisphere. However, in the case of the affected hand, the TMS results indicated either a purely ipsilateral projection or a bilateral projection in which the ipsilateral pathway had the lower motor threshold, whereas passive movement resulted in fMRI activation in the contralateral hemisphere. These results demonstrate that there is a significant fast‐conducting corticomotor projection to the affected hand from the ipsilateral hemisphere in this group of subjects, but that the predominant afferent projection from the hand is still directed to the affected contralateral hemisphere, resulting in an interhemispheric dissociation between afferent kinesthetic inputs and efferent corticomotor output. The findings indicate that there can be differences in the organization of sensory and motor pathways in cerebral palsy, and suggest that some of the residual motor dysfunction experienced by these subjects could be due to an impairment of sensorimotor integration at cortical level as a result of reorganization in the motor system. Ann Neurol 2001;49:320–327

Sleep problems in Rett syndrome

Rett syndrome (RTT) is a severe neurological disorder, affecting mainly females. It is generally caused by mutations in the MECP2 gene. Sleep problems are thought to occur commonly in Rett syndrome, but there has been little research on prevalence or natural history. An Australian population-based registry of cases born since 1976 has been operating since 1993, with current ascertainment at 300. The Australian Rett Syndrome Database (ARSD) consists of information about Rett syndrome cases including their functional ability, behaviour, sleep patterns, medical conditions and genotype. The cases range in age from 2 to 29 years. The aim of this study was to investigate the type and frequency of sleep problems, relationships with age and MECP2 mutation type and to evaluate changes over time. Parents or carers of the subjects with Rett syndrome were asked to complete a questionnaire about sleep problems on three separate occasions (2000, 2002 and 2004). Regression modelling was used to investigate the relationships between sleep problems, age and mutation type. Sleep problems were identified in over 80% of cases. The prevalence of night-time laughter decreased with age and the prevalence of reported night-time seizures and daytime napping increased with age. The prevalence of sleep problems was highest in cases with a large deletion of the MECP2 gene and in those with the p.R294X or p.R306C mutations. Sleep problems are common in Rett syndrome and there is some variation with age and mutation type.

Respiratory pattern changes in sleep in children on vagal nerve stimulation for refractory epilepsy.

BACKGROUND An altered breathing pattern in sleep, over two to three weeks, reported by the parents of a child on Vagal Nerve Stimulation (VNS) therapy for refractory epilepsy, prompted a sleep study in him. His polysomnography (PSG) revealed respiratory irregularity concordant with VNS activation. Dyspnoea is a well recognised and reported side effect of the VNS. However there are only a few studies looking at respiration in sleep with VNS. We therefore undertook PSGs in seven other children on VNS. METHODS Sleep studies were undertaken, in accordance with standard clinical practice. Sleep and apnoeas and hypopneas were scored in accordance with conventional criteria. Respiratory pattern changes in sleep (RPCS) with VNS were looked for. RESULTS Respiratory pattern changes in sleep were seen during PSG in seven of eight children on VNS for refractory epilepsy. Decreased effort and tidal volume occurred in seven children, concordant with VNS activation. In one child, this was associated with a fall in respiratory rate, i the other six children with an increase. No study showed an apnoea/hypopnoea index in the abnormal range. The RPCS were not associated with significant hypoxia or hypercapnoea. CONCLUSION Our results suggest that RPCS occur in most children with VNS. This is not surprising in view of the significant influence vagal afferents have on respiratory control centres. The RPCS did not appear to have a clinical impact in our group. However further investigations are suggested to explore this phenomenon, especially in patients with sleep apnoea syndromes or compromised respiratory function.

VNS therapy in clinical practice in children with refractory epilepsy

Objectives– To study the efficacy, tolerability and safety of the vagus nerve stimulation (VNS) therapy in clinical practice, in 16 children and adolescents with refractory epilepsy. Methodology– We assessed the efficacy of VNS therapy, retrospectively by comparing seizure frequency, duration and severity at the time of most recent follow up (av: 24.9 months) to that in the 4 weeks prior to VNS surgery. Changes in quality of life, sleep and behaviour at last review was compared with that prior to VNS. Adverse effects elicited by specific questioning, spontaneous reporting and clinical examination are described. Results– Vagus nerve stimulation resulted in a >50% reduction in seizure frequency in 62.5% of children with 25% achieving a >90% reduction. Vagus nerve stimulation was well tolerated in all but one of our cohort, with no serious side‐effects. Conclusion– Our results support its role as one of the options in intractable childhood epilepsy.

Valproate and risk of fracture in Rett syndrome

Objectives Some associations between antiepileptic drugs (AEDs) and fracture risk have been reported in the general population. This study investigated the relationships between fracture risk and commonly used AEDs in Rett syndrome, a genetic disorder associated with intellectual and physical disability. Study design Cases (n=233) were sourced from the population-based Australian Rett Syndrome Database and longitudinal data were used. The Cox proportional hazard model was used to analyse relationships between fracture and prescribed AEDs, mobility, epilepsy diagnosis and genotype. Results After controlling for mobility, epilepsy diagnosis and genotype, use of valproate increased the risk of fracture threefold after at least 1 year (HR 3.56; 95% CI 1.85 to 6.82) and after 2 or more years (HR 3.02; 95% CI 1.90 to 4.80). There was a lesser increased risk (HR 1.99; 95% CI 0.99 to 4.02) with lamotrigine in the first year of use but not for subsequent years of use. Carbamazepine slightly decreased the risk (HR 0.60; 95% CI 0.35 to 1.02) after 2 or more years of use. Conclusions The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect.

Photoparoxysmal responses in children: their characteristics and clinical correlates

This study evaluates the characteristics of photoparoxysmal responses elicited with intermittent photic stimulation during a routine electroencephalogram in childhood and correlated this with the clinical profile of the child. Photoparoxysmal responses occurred in 8% (21/263) of children where activation was undertaken. Photoparoxysmal responses were often brief and had a variable onset latency. This study suggests increasing the duration of the stimulus train to 10 seconds or more will increase the diagnostic yield. Photoparoxysmal responses very rarely outlasted the stimulus, and self-limited photoparoxysmal responses probably have greater significance than previously attributed to them. They are highly correlated with epilepsy.

Ictal Electroencephalograms in Neonatal Seizures: Characteristics and Associations

The characteristics of ictal electroencephalograms in 160 neonatal seizures of 43 babies were correlated with mortality and neurodevelopmental outcomes. Neonatal seizures are focal at onset, most frequently temporal, and often occur during sleep. Twenty-one percent of babies with seizures died, and 76% of survivors manifested neurodevelopmental impairment during 2-6-year follow-up. A low-amplitude ictal electroencephalogram discharge was associated with increased mortality, and a frequency of <2 Hz with increased morbidity. Status epilepticus, ictal fractions, multiple foci, and bihemispheric involvement did not influence outcomes. Of 160 seizures, 99 exhibited no associated clinical features (electrographic seizures). Neonatal seizures with clinical correlates (electroclinical seizures) exhibited a higher amplitude and frequency of ictal electroencephalogram discharge than electrographic seizures. During electroclinical seizures, the ictal electroencephalogram was more likely to involve larger areas of the brain and to cross the midline. Mortality and morbidity were similar in babies with electroclinical and electrographic seizures, emphasizing the need to diagnose and treat both types. Ictal electroencephalogram topography has implications for electrode application during limited-channel, amplitude-integrated electroencephalograms. We recommend temporal and paracentral electrodes. Video electroencephalograms are important in diagnosing neonatal seizures and providing useful information regarding ictal electroencephalogram characteristics.

Tetracycline-induced benign intracranial hypertension

Abstract: We report on a young adolescent with benign intracranial hypertension which we attribute to the use of minocycline for acne.

Neurodevelopmental outcomes in neonates with seizures: a numerical score of background encephalography to help prognosticate.

There is a high incidence of mortality and neurodevelopmental sequelae in babies with neonatal seizures. The electroencephalography (EEG) background has been shown to be an excellent predictor of outcome by most studies, with a few suggesting limited value in prognostication. Previous studies suggest poor prognosis with severely abnormal backgrounds, but prediction was difficult with moderate abnormalities. The proposed numerical scoring system for the EEG background provides an objective method of evaluation with improved reproducibility, categorization, and prognostication. Our study showed that the numerical score of EEG background was a good predictor of outcome. Higher numerical scores reflecting greater abnormality of background EEG were associated with increasing incidence of mortality, neurodevelopmental impairment, cerebral palsy, vision and hearing impairment, and epilepsy. The numerical score also correlated with neuroimaging abnormalities. A numerical EEG score can help target interventional strategies for neonatal seizures.