Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis followed by optic neuritis (ADEM-ON) is a rare demyelinating syndrome that is different from multiple sclerosis and neuromyelitis optica spectrum disorder. The aim of this study was to describe the disease course, treatment response and outcome of children with ADEM-ON. METHODS: Children of <18 years of age were identified from six countries of the EU Paediatric Demyelinating Disease Consortium. Patients fulfilled the diagnostic criteria for ADEM followed by at least one ON. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were tested in all patients. RESULTS: In this study of 17 patients (nine boys) with ADEM-ON, anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were identified in 16 patients. Age at onset was 6.1 years (interquartile range, 5.1-9.2 years). Twelve patients received oral prednisolone and 10 received maintenance immunosuppression (e.g. azathioprine, intravenous immunoglobulins, Rituximab). During a follow-up of 5.3 years (interquartile range, 1.8-10.2 years), 54 relapses occurred with a median of 3 relapses per patient (range, 1-9 per patient). Patients relapsed on all treatments but no relapses occurred on a prednisolone dose >10 mg/day. Visual and cognitive residual deficits were common in this group. CONCLUSIONS: Acute disseminated encephalomyelitis followed by optic neuritis is an anti-MOG antibody-associated relapsing disorder that can have a heterogeneous disease course. Patients were refractory for maintenance immunosuppression and appeared to be corticosteroid-dependent. Further international collaborations are now required to unify guidelines in this difficult-to-manage group of patients.

MRI as diagnostic tool in early-onset peroxisomal disorders.

OBJECTIVE: Peroxisomal blood tests are generally considered to be conclusive. We observed several patients with a clinical and MRI phenotype suggestive of an infantile onset peroxisomal defect, but no convincing abnormalities in initial peroxisomal blood tests. Brain MRI showed typical abnormalities as observed in the neonatal adrenoleukodystrophy variant of infantile peroxisomal disorders. Our aim was to evaluate the accuracy of this MRI diagnosis with further peroxisomal testing. METHODS: We searched our database of unclassified leukoencephalopathies and found 6 such patients. We collected clinical data and scored available MRIs of these patients. We performed further peroxisomal studies in fibroblasts, including immunofluorescence microscopy analysis with antibodies against catalase, a peroxisomal matrix enzyme. We performed complementation analysis and analyzed the suspected genes. RESULTS: We confirmed the diagnosis of Zellweger spectrum disorder in 3 patients and D-bifunctional protein deficiency in the others. The clinical findings were within the spectrum known for these diagnoses. Sequential MRIs showed that the abnormalities started in the hilus of the dentate nucleus and superior cerebellar peduncles. Subsequently, the cerebellar white matter and brainstem tracts were affected, followed by the parieto-occipital white matter, splenium of the corpus callosum, and posterior limb of the internal capsule. Eventually, all cerebral white matter became abnormal. The thalamus was typically affected as well. CONCLUSIONS: If MRI reveals abnormalities suggestive of infantile onset peroxisomal defects, negative peroxisomal blood tests do not exclude the diagnosis. Further tests in fibroblasts should be performed, most importantly immunofluorescence microscopy analysis with antibodies against catalase to stain peroxisomes.

Retention rate of Gabapentin in children with intractable epilepsies at 1 year.

Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a multi-centre retrospective observational study of the efficacy, tolerability and retention rate in 105 children, aged 0-17.5 years (mean 10.1) over a 14 year period. The median age of epilepsy onset was 2.5 years (range 0-14.6). 72% started GAB as at least the 3rd AED, with 43% having been withdrawn from at least 2 AEDs. 77% had focal and 52% symptomatic epilepsies. The maintenance doses for GAB ranged 6.0-87.3 mg/kg/day (mean 43.7). The study comprised 157 person-treatment years for GAB. GAB was well tolerated with 55% remaining on treatment beyond 1 year. No serious adverse events were reported whilst on GAB, but 39% reported possibly and probably related adverse events. Seizure improvement (<50% seizure frequency compared to baseline) at more than 12 months of treatment, was reported in 35% of patients starting GAB, including 6% who remained seizure free. The results demonstrated the efficacy and tolerability of GAB in children with difficult to treat epilepsies, and a good response to treatment beyond 12 months, in both focal and generalised epilepsies.

Paediatric multiple sclerosis: examining utility of the McDonald 2010 criteria.

The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We aimed to assess the utility of McDonald 2010 criteria in comparison with 2007 International Paediatric Multiple Sclerosis Study Group (IPMSSG)-recommended criteria for PMS diagnosis. Retrospective analysis of 38 PMS cases from three UK demyelination clinics was conducted. Dissemination in space (DIS) and time (DIT) for both McDonald and IPMSSG criteria were noted on initial and follow-up magnetic resonance imaging (MRI). At first MRI scan, IPMSSG DIS criteria were fulfilled in 68% of scans and McDonald DIS criteria in 84%. In total, 11/18 children given gadolinium contrast fulfilled both McDonald DIS and DIT criteria on initial scan. The 2010 McDonald criteria appear more sensitive than IPMSSG and may allow PMS diagnosis at first presentation of CIS in at least a half of cases.

Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis.

New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool. Fifty-one IPMSSG members from 21 countries responded to the survey, and 50 approved the final statement. Consensus recommendations regarding use of existing first- and second-line therapies, as well as a proposed definition for inadequate treatment response, are presented. Recommendations for the use and evaluation of emerging therapies (currently in phase III clinical trials or recently approved for adult MS) are discussed. The IPMSSG endorses the inclusion of pediatric MS patients in trials evaluating appropriate new and emerging therapies. Mechanisms for conducting high-impact, multicenter studies, including long-term follow-up in pediatric MS, are required to ensure that all MS patients, irrespective of age, benefit from advances in MS therapeutics.

Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease.

Pelizaeus-Merzbacher-like disease (PMLD) is a clinically and genetically heterogeneous neurological disorder of cerebral hypomyelination. It is clinically characterised by early onset (usually infantile) nystagmus, impaired motor development, ataxia, choreoathetoid movements, dysarthria and progressive limb spasticity. We undertook autozygosity mapping studies in a large consanguineous family of Pakistani origin in which affected children had progressive lower limb spasticity and features of cerebral hypomyelination on MR brain imaging. SNP microarray and microsatellite marker analysis demonstrated linkage to chromosome 1q42.13-1q42.2. Direct sequencing of the gap junction protein gamma-2 gene, GJC2, identified a promoter region mutation (c.-167A>G) in the non-coding exon 1. The c.-167A>G promoter mutation was identified in a further 4 individuals from two families (who were also of Pakistani origin) with clinical and radiological features of PMLD in whom previous routine diagnostic screening of GJC2 had been reported as negative. A common haplotype was identified at the GJC2 locus in the three mutation-positive families, consistent with a common origin for the mutation and likely founder effect. This promoter mutation has only recently been reported in GJC2-PMLD but it has been postulated to affect the binding of the transcription factor SOX10 and appears to be a prevalent mutation, accounting for ~29% of reported patients with GJC2-PMLD. We propose that diagnostic screening of GJC2 should include sequence analysis of the non-coding exon 1, as well as the coding regions to avoid misdiagnosis or diagnostic delay in suspected PMLD.

Severe acute disseminated encephalomyelitis: a paediatric intensive care population-based study.

There is a paucity of literature on the epidemiology of severe acute disseminated encephalomyelitis (ADEM). We describe a Paediatric Intensive Care Unit (PICU) population-based study to determine the epidemiology and clinical characteristics of children with ADEM requiring PICU admission or resulting in death. Anonymized data from the Paediatric Intensive Care Audit Network (PICANet) were obtained for all children under 16 years with a diagnosis of ADEM admitted to 25 PICUs in England and Wales (2004-2008). The Office for National Statistics (ONS) mortality database was also searched. In total, 27 PICANet cases (13 females:14 males; median age 4.8 years) were ascertained and all were alive on discharge. In addition, three cases were identified from the ONS mortality database. Of the 27 PICANet cases, clinical features included; seizures (n = 5); upper airway respiratory obstruction/stridor (n = 2); unspecified encephalopathy (n = 27); and polyfocal neurological deficits (n = 6). The median duration of ventilation was 3 days. Inotropic support was required in 4/27 patients, and one patient had invasive intracranial pressure monitoring. None received plasmapheresis. We conclude that the incidence of childhood ADEM admitted to the PICU in England and Wales is approximated at 0.5 per million children/year, thus representing approximately one quarter of children admitted with ADEM (denominator: 2009 Canadian surveillance data).

Genotype-phenotype correlation in vanishing white matter disease.

OBJECTIVE: Vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy characterized by slowly progressive ataxia and spasticity with additional stress-provoked episodes of rapid and major deterioration. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B, which is pivotal in translation of mRNAs into proteins. The disease onset, clinical severity, and disease course of VWM vary greatly. The influence of genotype and gender on the phenotype is unclear. METHODS: From our database of 184 patients with VWM, we selected those with the following mutations in the gene EIF2B5: p.Arg113His in the homozygous state (n = 23), p.Arg113His in the compound-heterozygous state (n = 49), p.Thr91Ala in the homozygous state (n = 8), p.Arg113His/p.Arg339any (n = 9), and p.Thr91Ala/p.Arg339any (n = 7). We performed a cross-sectional observational study. Evaluated clinical characteristics were gender, age at onset, age at loss of walking without support, and age at death. Means, male/female ratios, and Kaplan-Meier curves were compared. RESULTS: Patients homozygous for p.Arg113His had a milder disease than patients compound heterozygous for p.Arg113His and patients homozygous for p.Thr91Ala. Patients with p.Arg113His/p.Arg339any had a milder phenotype than patients with p.Thr91Ala/p.Arg339any. Overall, females tended to have a milder disease than males. CONCLUSIONS: The clinical phenotype in VWM is influenced by the combination of both mutations. Females tend to do better than males.

Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).

BACKGROUND: Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders in which disruption of cellular mechanisms leads to accumulation of iron in the basal ganglia. This group includes patients with recently discovered mutations in the PLA2G6 gene encoding a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Previously, children with PLA2G6 mutations have been diagnosed with several different disorders and we wished to better define the phenotype of PLA2G6- associated neurodegeneration. METHODS: Detailed review of the clinical and genetic features of 14 and radiologic features of 13 of these patients with PLA2G6 mutations was undertaken. RESULTS: Median age of symptom presentation was 14 months. One third of the cohort presented following an intercurrent illness. The children had progressive cognitive and motor skill regression, with evidence of axial hypotonia, four limb spasticity, bulbar dysfunction, and strabismus. All patients developed cerebellar ataxia and dystonia. Most patients had optic atrophy. Brain imaging demonstrated cerebellar cortical atrophy and gliosis in all patients. Changes consistent with increased iron deposition were identified in the globus pallidus and substantia nigra. Novel corpus callosum changes are also reported. CONCLUSION: We describe a cohort of patients with PLA2G6-associated neurodegeneration (PLAN). Although patients with PLAN have previously been diagnosed with infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome, they display a characteristic clinical and radiologic phenotype. PLA2G6 mutational analysis will negate the need for more invasive diagnostic procedures such as tissue biopsy.

How do paediatricians communicate with children and parents?

AIM: The outpatient clinic visit is the major focus of the hospital medical process for most paediatricians, children and parents. The importance of children as active participants in this interaction has been recognized. Our study aims are to describe and assess the components of doctor-parent-child communication in the outpatient setting. METHODS: Fifty-one medical paediatric clinic consultations were recorded on audio cassette, and communication was analysed according to quantitative methods. Questionnaires assessed parents' and children's perceptions. RESULTS: Doctors contributed most to the conversation (61%), children only 4%. Behaviour: Doctors' communication was 84% instrumental (e.g. asking questions, giving information or instructions), 13% affective behaviour (expressing concerns and worries) and 3% social (small talk). Parents' communication included giving information (83%), seeking information (13%) and social (4%). The child asked less information (3%) and had more social conversation (19%). CONTROL: Doctors dominated in turn taking (52%). Children took 9% of all turns. Perception: There was no correlation between parents' and children's perception and the informative or affective behaviour of the doctor. CONCLUSION: Communication is mainly instrumental. Doctors tend to direct the interview. Children's contribution is small. The participation of children needs to be encouraged as part of a patient-centred approach.

Saline infusion: a diagnostic and therapeutic tool in nonepileptic attacks?

OBJECTIVE: Nonepileptic attacks (NEAs) pose diagnostic and therapeutic uncertainties. Prognosis is poor. Activation procedures like saline infusion have been used for diagnostic purposes. METHOD: We reviewed 66 consecutive patients with a probable diagnosis of NEA. During the EEG an attempt was made to induce an attack with verbal suggestion and saline infusion. Patients were followed up with a postal or telephone questionnaire 4.5 years after the EEG. RESULTS: Saline infusion with verbal suggestion induced in 41 of 66 patients a NEA, i.e., a positive test. Thirty-one patients were followed up. Attacks were reduced in 20 patients, of whom 12 were attack-free. More patients were attack-free at follow-up after a positive (7 of 16) in comparison to a negative (5 of 15) test. CONCLUSION: A provocative test can be diagnostic in some patients with NEA. An early and firm diagnosis may lead to appropriate treatment and better outcome.

Acute disseminated encephalomyelitis: a review of 18 cases in childhood.

OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) is a treatable inflammatory demyelinating disorder seen more commonly in children than in adults. It typically presents to general paediatricians, often, like encephalitis, with non-specific cerebrospinal fluid findings. The brain computerized tomography scan is usually normal, so is falsely reassuring and delays the diagnosis, which might result in considerable morbidity. The present study was initiated to report on the various modes of presentation and raise the awareness of the diagnosis of ADEM among general paediatricians. METHODS: A retrospective review of the case notes of 18 children with a diagnosis of ADEM established in a tertiary referral centre from 1995 to 2000 was undertaken with particular reference to clinical features, investigations and treatment. RESULTS: The most common presenting features were ataxia (10 cases), followed by headache (eight cases) and weakness (five cases). Magnetic resonance imaging (MRI) of the brain was needed to confirm the diagnosis in all 18 children. Treatment usually included a course of intravenous methylprednisolone followed by a tapering dose of oral prednisolone over several weeks. Although the outcome for most of the children was generally good, two relapsed after cessation of steroids and five children had ongoing disabilities. CONCLUSIONS: The investigation of choice for establishing the diagnosis of ADEM was MRI of the brain. Other investigations were seldom helpful in reaching the diagnosis. Early diagnosis and prompt treatment of ADEM will probably reduce morbidity.

Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians.

Acute disseminated encephalomyelitis will often present to the general paediatrician as an acute polysymptomatic encephalopathy, and initially the diagnosis may not be clear. A brain MRI scan is essential in establishing the diagnosis and so enabling appropriate advice and treatment to be given. Multicentre clinical audit of outcome and controlled therapeutic trials are needed to secure an evidence base for current practice.

Idiopathic gait disorder among in-patients with acquired gait disorders admitted to a children's hospital.

Many children are admitted to hospital for treatment of an acquired gait disorder. Some gait disorders have a definite underlying physical cause and some are idiopathic. A literature review shows that there have been few attempts to estimate the incidence or prevalence of idiopathic gait disorder in children. The economic and social impact may be substantial with regard to therapy and investigations and school absence, respectively. This study attempted to estimate the incidence and impact of idiopathic gait disorder in a tertiary children's hospital. It evaluated prospectively all the children admitted with a gait disorder requiring physiotherapy treatment at Birmingham Children's Hospital, using a standardized pro-forma, during a 3-month period between March-June 1999. One hundred and three children (aged 2-16 years) were admitted with gait disorders (57 female and 46 male). Eight had an idiopathic gait disorder. All eight children exhibited significant functional impairment, pain and school absence. Idiopathic gait disorder accounted for 8% of children admitted to hospital with an acquired gait disorder and had an annual incidence of at least 2-4 per 100,000 children. The economic and social impact of these disorders is, therefore, substantial, especially with regard to diagnosis, investigations, treatment and school absence.

Comparative audit of intravenous lorazepam and diazepam in the emergency treatment of convulsive status epilepticus in children.

There is little evidence on which to judge the optimal treatment for convulsive status epilepticus (CSE) in children. This study compares the effect of intravenous (iv) lorazepam with iv diazepam as the first line of treatment of CSE. We studied all children with prolonged seizures arriving in the Accident and Emergency (A&E) Department in two separate periods. In the first 6-month period iv diazepam was used as standard treatment, in the second 1-year period iv lorazepam was used. We measured latency to stopping of seizure and any adverse events. A successful treatment was defined as one in which the seizure clinically ceased within 15 minutes after siting the iv cannula, requiring no further treatment.Intravenous diazepam (0.32 mg kg (-1)) was used in 17 of 26 patients, whilst iv lorazepam (0.13 mg kg (-1)) was used in 31 of 59. There were no differences between the two groups regarding age, sex and seizure type.The seizure was successfully controlled 15 minutes after siting the iv cannula in 11 (65%) patients treated with diazepam (median time of 3 minutes) and in 20 (65%) patients treated with lorazepam (median time of 5 minutes). These preliminary results suggest that iv lorazepam may be as effective as iv diazepam.

Melatonin is useful for recording sleep EEGs: a prospective audit of outcome.

The study aimed to determine if melatonin could reliably induce sleep in children undergoing sleep EEG without affecting the usefulness of the EEG itself. One hundred and sixty three children (112 males, 51 females; mean age 8 years, range 1 to 16 years) referred for sleep EEG were studied. The children were given 2 to 10 mg of melatonin, depending on age, just before EEG recording. Measurements included sleep-onset latency, adverse effects, and acceptability of the EEG. Usefulness and acceptability of melatonin-induced sleep EEG were compared with the standard technique of sleep EEG following sleep deprivation in 30 children (matched for sex and age). Sleep was obtained in 79% of the 163 children who received melatonin after an average of 33 minutes. Yield of epileptiform abnormalities demonstrated in the melatonin sleep EEG was similar to that reported in the literature for sleep-deprived EEGs. There was no significant adverse effect. When compared, a melatonin-induced sleep EEG was as useful as a sleep-deprived EEG. However, the children's behaviour on the day of the melatonin-induced sleep EEG recording was more acceptable to parents.

Siblings with development delay, mild spasticity and subcortical cysts: a further leukoencephalopathy?

We present a family with mild neurological symptoms and intra-cerebral subcortical cysts on magnetic resonance imaging (MRI). Common clinical features are microcephaly, learning difficulties, spasticity, dyspraxia and restricted movements of the neck and shoulder. The family has features in common with vacuolating leukoencephalopathy of van de Knaap and Olivier and may represent a new variant.

Idiopathic central pontine myelinolysis in childhood.

Central pontine myelinolysis (CPM) is rare in childhood with only a few cases reported in world literature. We report a 7-year-old male who presented with acute ataxia, swallowing difficulties, dysarthria, and radiological features consistent with the disorder. He improved remarkably with oral prednisolone therapy and was almost back to normal by 2 weeks. A review of the literature is also included.

Melatonin as a sleep inductor for electroencephalogram recordings in children.

OBJECTIVE: To determine the efficacy of melatonin in obtaining sleep electroencephalograms in children. METHODS: Melatonin was used in 68 unselected children referred to the neurophysiology department for sleep electroencephalogram (EEG). A group of 68 children matched for age and sex who underwent EEGs after sleep deprivation in the same period was used as control. Sleep latency, as well as latency from stage 1 to stages 2, 3 and 4 were measured. RESULTS: No difference in the number of children who went to sleep was seen. No significant difference is the macrostructure of sleep was seen, other than a reduced sleep latency for the melatonin group (P<0.01). CONCLUSION: The study suggests that melatonin can reliably be used for obtaining sleep EEGs in children. Its use seems to provide a good alternative to pharmacological sedation and a complementary method to sleep deprivation.