Neuroimaging in non-accidental head injury in children: an important element of assessment.

Head injury from physical abuse is unfortunately a common occurrence in our society. It is a major cause of mortality and long-term physical and psychological disability in children. Diagnosis of non-accidental head injury may be difficult, as most infants present with non-specific clinical findings and without external signs of trauma. Neuroimaging plays a fundamental role both for medical management and medicolegal aspects of child abuse. It is therefore imperative for the radiologist to promptly recognise the radiological findings of various forms of non-accidental head injury to render a more accurate opinion. A standardised imaging protocol and good communication between professionals are essential for optimum management.

Vagus nerve stimulation in children with intractable epilepsy: indications, complications and outcome.

PURPOSE: To analyze the indication, complications and outcome of vagus nerve stimulation in intractable childhood epilepsy. MATERIALS AND METHODS: We retrospectively reviewed the data of 69 children who had insertion of vagal nerve stimulator (VNS) between June 1995 and August 2006 for medically intractable epilepsy. Outcome was based on the Engel's classification. Statistical analysis of the data was also done to see if any of the parameters significantly influenced the outcome. RESULT: Thirty-eight patients (55.08 %) had a satisfactory outcome (Engel class I, II or III), and in 31 patients (44.92 %), there was no worthwhile improvement of seizures (Engel class IV). There was no statistical significance between the type of seizure and outcome (Fisher's exact test, p = 0.351). Statistical analysis also showed that the following parameters did not significantly influence the outcome (p > 0.05): age at insertion of VNS, age of first fit, duration between first fit and insertion of VNS and the length of follow-up. Complications included infection, lead fracture, fluid collection around the stimulator, neck pain and difficulty swallowing. CONCLUSION: Vagus nerve stimulation is a relatively safe and potentially effective treatment for children with medically intractable epilepsy.

Retention rate of levetiracetam in children with intractable epilepsy at 1 year.

UNLABELLED: Levetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently obtained marketing authorisation for use in children. The purpose of this study was to assess the efficacy, tolerability and retention rate of LEV in children with refractory epilepsies. It is a retrospective multicentre observational study reporting the use of LEV in 200 children, aged 0.3-19 years (median 9-years-old) over a 4-year period. All of the patients included in the study had refractory epilepsy with a median age of onset of epilepsy of 3 years (range 0-13 years). The 38% had failed and withdrawn 3 or more AEDs previously and 24% were taking at least 2 other AEDs in addition to LEV. The 47% had focal, and 58% had symptomatic epilepsies. The LEV dose ranged from 8 to 100 mg/kg/day (mean 39 mg/kg). The study comprised 215 person years of LEV exposure. RESULTS: LEV was well tolerated with a retention rate of 49% at 1 year. No serious adverse events were reported with possibly related adverse events reported in only 24% of patients (mainly emotional or behavioural changes). At more than 2, 6 and 12 months, worthwhile improvement (>50% seizure reduction) was noted in 60, 40 and 32%, including seizure freedom in 14, 14 and 5%, respectively. CONCLUSION: Our results confirm the efficacy and tolerability of LEV in children with refractory epilepsies and demonstrate good response and retention rates at 12 months. It represents the largest cohort of paediatric patients published so far on LEV with a 1-year follow-up.

A second locus for Aicardi-Goutieres syndrome at chromosome 13q14-21.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.

Congenital trigeminal anaesthesia.

Two patients with congenital trigeminal nerve anaesthesia are described. The first (male, aged 14 years) had an isolated unilateral loss of sensation in all three divisions of the trigeminal nerve with no other abnormalities. The second patient (male, aged 3 years 6 months) had bilateral loss of sensation in all three divisions of the trigeminal nerve, associated with other neurological abnormalities. No explanation for their abnormalities was found. The Rosenberg classification of congenital trigeminal anaesthesia is discussed with reference to these patients and also with reference to the developmental biology of the trigeminal nerve.

The use of regional anaesthetic blockade in a child with recurrent erythromelalgia.

Primary erythromelalgia is a rare condition, which is characterised by redness, burning pain, and increased temperature of the extremities. We describe a 6 year old boy with symptoms of erythromelalgia and the difficulty surrounding treatment of this condition. Severe pain responded to the use of regional anaesthetic blocks.

A magnetic resonance study of complicated early childhood convulsion.

OBJECTIVES: The relation between complicated early childhood convulsion (ECC) and adult epilepsy is unclear, although a history of complicated ECC is obtainable in half of adults with epilepsy associated with hippocampal sclerosis. It is not known if the ECC is a marker of pre-existing brain damage or is itself harmful to the developing brain. The objective of the study was to assess the extent of structural brain abnormality present soon after a first complicated early childhood convulsion with a view to obtaining data which might contribute to an understanding of whether such abnormalities were likely to be pre-existing or caused by the convulsion. METHODS: Children under the age of 5 years were recruited into the study after their first complicated febrile or non-febrile ECC. None had previously experienced an epileptic seizure. All underwent MRI of the brain within 14 days. Hippocampal volumes and T2 relaxation times were measured. The results were compared with a neurological control group of children without gross structural abnormalities of the neocortex undergoing MRI of the brain for reasons other than epilepsy. RESULTS: Eighteen patients and 10 control subjects were recruited into the study. One patient was subsequently excluded because of EEG and clinical evidence of benign childhood epilepsy. Nine patients had volumetric evidence of significant hippocampal volume asymmetry (3 SD from the mean of the control group), although in only three of these was the asymmetry apparent on visual inspection of the MRI. Three patients had extrahippocampal neuropathology. None of the control subjects had significant hippocampal volume asymmetry (p<0.001). T2 relaxometry showed no evidence that postictal hippocampal oedema contributed to the asymmetry. CONCLUSIONS: There is a high prevalence of structural brain abnormalities in children within 2 weeks of the first complicated early childhood convulsion, including significant hippocampal asymmetry unrelated to oedema. This does not exclude a damaging effect of complicated ECC on the brain, but suggests that in at least some patients the complicated ECC is the result of pre-existing brain abnormalities.

Severe infantile axonal neuropathy with respiratory failure.

We describe 5 infants (4 male, 1 female) with a severe intractable form of motor-sensory axonal neuropathy. All became ventilator-dependent, 4 have since died and 1 remains static. Diaphragmatic paralysis was an early feature with generalized neuropathy evolving rapidly. Nerve conduction studies and biopsies were consistent with axonal disease. This disorder could be a new condition or part of the spectrum of inherited neuropathies of the axonal degenerative type. It may be that there is a "switching-off" in the infant's Schwann cell-axonal interactions in utero or in the early postnatal period, resulting in severe progressive deterioration and then a static period without recovery.

Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21.

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

Aicardi-Goutières syndrome: monogenic recessive disease, genetically heterogeneous disease, or multifactorial disease?

Aicardi-Goutières syndrome (AGS) is a severe progressive familial encephalopathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome-wide screening of five consanguineous families was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals could be found. Regions of homozygosity in affected sibs could only be identified within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are clinically difficult to distinguish from AGS. Involvement of a small number of genes and/or of an external factor, such as infection, may also explain the absence of a homozygous region common to all affected individuals.

The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease.

Thirty-three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary ourotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0 mumol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0 mumol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl-phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.

Recognizable inherited syndrome of progressive central nervous system degeneration and generalized intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutières.

Five boys and two girls from a large consanguineous British Muslim family of Pakistani origin are described. All presented from infancy to early childhood with progressive moderate to severe developmental delay, postnatal microcephaly, spastic quadriplegia, refractory seizures, and visual handicap. Cerebrospinal fluid (CSF) pleocytosis was present in three children. Neuroimaging with computerized tomography on three boys and a girl showed generalized cortical atrophy, dilatation of the lateral, third, and fourth ventricles, widening of the surface CSF spaces, hypoplasia of the posterior fossa structures, and multiple and solitary calcifications in the cerebral cortex and punctate calcifications involving basal ganglia, cerebellum, and the Sylvian fissure. Histopathological examination of the brain from three boys and one girl confirmed generalized cortical and cerebellar atrophy with widespread calcifications within the cortical grey and white matter, the basal ganglia, the cerebellum, and in some areas along the capillaries. Investigations excluded a possible nongenetic cause. Parental consanguinity favor autosomal recessive inheritance. This appears to be a recognizable syndrome overlapping the syndrome of Aicardi and Goutières (MIM 225750).

Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex.

We describe two children with complex cortical malformations as well as the typical intracranial manifestations of tuberous sclerosis complex. One child had hemimegalencephaly and the other had extensive focal megalencephaly. These cases are discussed in terms of the current concepts of cortical malformations.

Case summary: Benjamin.

Benjamin was diagnosed with Aspberger's syndrome on starting school. Prior to that, at the age of five years he presented with seizures involving deviation of the head and eyes to the right and jerking of the limbs. EEG was very abnormal with multifocal paroxysmal activity and occasional bursts of spike and slow wave activity. CT scan and MRI were normal and investigations failed to identify any underlying aetiology for the seizures. Carbamazepine was initially successful in controlling the seizures but improvement was not sustained despite maximal tolerated doses. A similar course of events was seen with sodium valproate, initially in combination with ethosuximide (for emergent tonic-clonic and absence seizures), then with vigabatrin (which unmasked myoclonic seizures), clonazepam and finally lamotrigine. The EEG remained abnormal even during periods of improved seizure control and there was no improvement in his Aspberger's syndrome. His epilepsy syndrome has not been classified. Subsequent treatment options include lamotrigine monotherapy.

Juvenile neuronal ceroid-lipofuscinosis: developmental progress after supplementation with polyunsaturated fatty acids.

Six patients with juvenile neuronal ceroid-lipofuscinosis (NCL) who were demonstrated to have abnormally low levels of membrane phospholipids were treated by dietary supplementation with polyunsaturated fatty acids (PUFAs) for periods ranging from 4 years 10 months to 7 years 3 months. Annual evaluations of intelligence and fine motor ability were undertaken while on supplementation. Mental development remained stable in most subjects throughout this period; fine motor function and vision were stable in the two youngest subjects only. These data suggest that PUFA supplementation may arrest the natural course of juvenile NCL if treatment is started early. A larger, multicenter, controlled trial is warranted.