Effect of lamotrigine on cognition in children with epilepsy.

BACKGROUND: Lamotrigine does not affect cognition in healthy adult volunteers or adult patients with epilepsy, but its effect on cognition in children is uncertain. OBJECTIVE: To compare the effect of lamotrigine and placebo on cognition in children with well-controlled or mild epilepsy. METHOD: In a double-blind, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Each treatment phase was 9 weeks, the crossover period 5 weeks. A neuropsychological test battery was performed during EEG monitoring at baseline and at the end of placebo and drug phases. The paired Student' t test was used for statistical analysis for neuropsychological data (two tailed) with a p value of 0.01 considered significant. Carryover and period effect were analyzed with generalized linear modeling (SPSS 10). RESULTS: Forty-eight children completed the study. Seizure frequency was similar during both treatment phases. No significant difference was found in continuous performance, binary choice reaction time, verbal and nonverbal recognition, computerized visual searching task, verbal and spatial delayed recognition, and verbal and nonverbal working memory between placebo and lamotrigine treatment phase. There was no significant carryover and period effect when corrected for randomization. CONCLUSION: Lamotrigine exhibits no clinically significant cognitive effects in adjunctive therapy for children with epilepsy.

The impact of PET scanning on management of paediatric oncology patients.

PURPOSE: Limited information is available on the use of positron emission tomography (PET) in paediatric oncology. The aim of this study was to review the impact of PET on the management of paediatric patients scanned over a 10-year period. METHODS: One hundred and sixty-five consecutive oncology patients aged 11 months to 17 years were included. Two hundred and thirty-seven scans were performed. Diagnoses included lymphoma (60 patients), central nervous system (CNS) tumour (59), sarcoma (19), plexiform neurofibroma with suspected malignant change (13) and other tumours (14). A questionnaire was sent to the referring clinician to determine whether the PET scan had altered management and whether overall the PET scan was thought to be helpful. RESULTS: One hundred and eighty-nine (80%) questionnaires for 126 patients were returned (63 relating to lymphoma, 62 to CNS tumours, 30 to sarcoma, 16 to plexiform neurofibroma and 18 to other tumours). PET changed disease management in 46 (24%) cases and was helpful in 141 (75%) cases. PET findings were verified by histology, clinical follow-up or other investigations in 141 cases (75%). The returned questionnaires indicated that PET had led to a management change in 20 (32%) lymphoma cases, nine (15%) CNS tumours, four (13%) sarcomas, nine (56%) plexiform neurofibromas and four (22%) cases of other tumours. PET was thought to be helpful in 47 (75%) lymphoma cases, 48 (77%) CNS tumours, 24 (80%) sarcomas, 11 (69%) neurofibromas and 11 (61%) cases of other tumours. PET findings were verified in 44 (70%) lymphoma cases, 53 (85%) CNS tumours, 21 (70%) sarcomas, 12 (75%) neurofibromas and 11 (61%) other tumour cases. CONCLUSION: PET imaging of children with cancer is accurate and practical. PET alters management and is deemed helpful (with or without management change) in a significant number of patients, and the results are comparable with the figures published for the adult oncology population.

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections.

BACKGROUND: Polymerase chain reaction (PCR) is used to detect viruses in the cerebrospinal fluid (CSF) of patients with neurological disease. However, data to assist its use or interpretation are limited. OBJECTIVE: We investigated factors possibly influencing viral detection in CSF by PCR, which will also help clinicians interpret positive and negative results. METHODS: CSF from patients with was tested for human herpesviruses types 1-6, JC virus, enteroviruses, and Toxoplasma gondii. The likelihood of central nervous system (CNS) infection was classified as likely, possible, or unlikely. PCR findings in these categories were compared using single variable and logistic regression analysis. RESULTS: Of 787 samples tested, 97 (12%) were PCR positive for one or more viruses. Of episodes likely to be CNS viral infections, 30% were PCR positive compared to 5% categorised as unlikely. The most frequent positive findings were Epstein Barr virus (EBV), enteroviruses, and herpes simplex virus (HSV). Enteroviruses and HSV were found predominantly in the likely CNS viral infection group, whereas EBV was found mainly in the unlikely group. Positive PCR results were more likely when there were 3-14 days between symptom onset and lumbar puncture, and when CSF white cell count was abnormal, although a normal CSF did not exclude a viral infection. CONCLUSIONS: The diagnostic yield of PCR can be maximised by using sensitive assays to detect a range of pathogens in appropriately timed CSF samples. PCR results, in particular EBV, should be interpreted cautiously when symptoms cannot readily be attributed to the virus detected.

Lower limb extensor moments in children with spastic diplegic cerebral palsy.

In this retrospective study, we quantified the mean extensor moment at the ankle, knee and hip over the stance period in a group of independently ambulant children with spastic diplegia (n = 90; 167 limbs) and in a group of normally-developing (ND) children (n = 22; 22 limbs). The mean knee extensor moment and the mean support moment demonstrated greater variance in children with diplegia than in normally-developing children (P < 0.0001 and P < 0.001). This was explained by a strong relationship between the mean knee extensor moment and minimum knee flexion in stance (r2 = 0.615; P < 0.0001) in the affected group with a positive mean knee extensor moment for all those children who walked in greater than 20 degrees of knee flexion. We also found a linear relationship between the support moment and knee flexion (r2 = 0.805; P < 0.0001). Our data supported the biomechanical analysis of Hof [Gait Posture, 12 (2000) 196] who suggested that his modified support moment should be a linear function with eccentricity at the knee. Extensor moments at the ankle (r2 = 0.001376; P = 0.641) and hip (r2 = 0.0860; P = 0.000168) bore weak relationships with increasing knee flexion even though there was a strong positive relationship between minimum knee flexion and minimum hip flexion (r2 = 0.316; P < 0.0001). We conclude that children with spastic diplegic cerebral palsy (SDCP) who walk with a crouch gait rely on their knee extensors to prevent collapse of the lower limbs. Intervention directed at redistributing extensor moments between the joints of the lower limbs may slow the increase in knee flexion and prolong reasonable walking function in this group.

Infantile Parkinsonism-dystonia and elevated dopamine metabolites in CSF.

Two girls and one boy are described, with severe infantile parkinsonism-dystonia. This syndrome is usually caused by endogenous dopamine deficiency but in these patients was associated with elevated dopamine metabolites in CSF and an unusual eye movement disorder: ocular flutter together with saccade initiation failure. Pyramidal tract signs also emerged in the course of the disease in two patients. This combination of symptoms and biochemical findings suggests a unique pathogenic mechanism.

Accurate measurement of muscle belly length in the motion analysis laboratory: potential for the assessment of contracture.

Two-dimensional ultrasound imaging was combined with motion analysis technology to measure distances between remote anatomical landmarks. The length of the belly of the medial gastrocnemius muscle in five normal adults (nine limbs) was estimated using this technique. Our results in vivo were similar to the reported data for the lengths of muscles in cadavers, and were consistent with the expected relationship between muscle belly length and ankle joint angle. Experiments in vitro demonstrated that the accuracy of the device was better than 2 mm over 20 cm. Measurements on the same subject on different occasions showed that the results were repeatable in vivo. Rendering of the reconstructed volume of a foam phantom gave results comparable to photographic images. This validated technique could be used to measure muscle lengths in children with spastic cerebral palsy and indicate which muscles had fixed shortening, and to what extent.

Lower limb and back pain in Guillain-Barré syndrome and associated contrast enhancement in MRI of the cauda equina.

UNLABELLED: This study assesses the frequency of lower limb and back pain in children with Guillain-Barré syndrome and reviews the magnetic resonance imaging results of those undergoing spinal imaging. Over an 8-y period, nine children presented with various combinations of severe back pain, leg pains, impairment of gait and bladder dysfunction. Guillain-Barré syndrome was confirmed on clinical examination and peripheral electrophysiology (n = 8). Magnetic resonance imaging in four patients, following contrast injection, showed enhancement of the cauda equine and, additionally, of the cervical nerve roots in one of the patients. A further patient, who was not scanned with contrast, had abnormal thickening of the lumbar roots. Carbamazepine and steroids were effectively used for analgesia in three cases. All the patients recovered. CONCLUSION: Guillain-Barré syndrome should be considered in the differential diagnosis of children presenting with back and/or leg pain. Early diagnosis ensures prompt monitoring for autonomic dysfunction and respiratory compromise.

Landau-Kleffner syndrome: course and correlates with outcome.

The presenting characteristics of 18 (11 female, seven male) children with Landau-Kleffner syndrome (LKS) were studied with respect to course and outcome of their condition at a mean length of 67 (SD 46) months' follow-up. All had regression of receptive language (mean age of onset 4 years 9 months) and electrical status epilepticus in sleep (ESES). Length of ESES correlated strongly with length of period between onset of illness and onset of recovery (p<0.006) and also with eventual receptive (p<0.001) and expressive (p<0.007) language. Behaviour during the acute phase was severely affected in nine children and associated with frontal lobe discharges in awake EEGs (p<0.004). Age at onset was not correlated with outcome. All children had impaired short-term memory at follow-up. Three children had language outcome within the normal range. No child with ESES lasting longer than 36 months had normal language outcome. These data lend support for intervention in ending ESES by 36 months using multiple subpial transection (MST) if steroids are ineffective or cause unacceptable side effects.

Multiple subpial transection in Landau-Kleffner syndrome.

We have considered multiple subpial transection (MST) as a treatment option for Landau-Kleffner syndrome (LKS) for the past 6 years. The effect of this technique on language and cognitive ability, behaviour, seizures, and EEG abnormalities is analysed here. Five children (4 males, 1 female; aged 5.5 to 10 years) underwent MST with sufficiently detailed pre- and postoperative data for analysis. Behaviour and seizure frequency improved dramatically after surgery in all children. Improvement in language also occurred in all children, although none improved to an age-appropriate level. All five had electrical status epilepticus in sleep (ESES) before surgery, which was eliminated by the procedure. One child has had an extension of his MST due to the recurrence of ESES and accompanying clinical deterioration with good effect. An attempt is made to set the effect of MST against the natural history of the condition. MST is an important treatment modality in LKS, although the timing of this intervention and its effect on final language outcome remains to be defined.

Architecture of the medial gastrocnemius in children with spastic diplegia.

Ultrasound images were obtained of the medial gastrocnemius at different ankle joint positions with the knee extended. Fascicle length and deep fascicle angle were measured in five normally developing adults (mean age 33 years, age range 24 to 36 years) and in five normally developing children (mean age 7.8 years, age range 7 to 11 years), and in seven children with spastic diplegia (mean age 10 years, age range 6 to 13 years). These architectural variables were similar in the groups of normally developing adults and children. Importantly, no statistical difference could be found between the normally developing children and those with diplegia for fascicle length. Deep fascicle angles were reduced significantly in the clinical group at a particular ankle joint angle but not at the resting angles. The difference in deep fascicle angles is explained as a function of resting muscle length and is not attributed any clinical importance. Our results do not explain the structural origin of muscle contracture explicitly. However, they do indicate that most of the fixed shortness in the medial gastrocnemii of ambulant children with spastic diplegia is not due to reduced muscle fascicle length. We suggest that muscle contracture may be better explained in terms of shortness of the aponeuroses of pennate muscles, such as the medial gastrocnemius, through reduced muscle fascicle diameter.

Cerebellar ataxia, anterior horn cell disease, learning difficulties, and dystonia: a new syndrome.

The following case reports describe a new condition of cerebellar ataxia, anterior horn cell disease, dystonia, and learning difficulties. Four cases are described. The condition appears to be of autosomal recessive inheritance as the group is made up of two pairs of sisters. All cases were evident by 3 years of age. Anterior horn cell disease was of a type not previously described at this age in association with cerebellar ataxia. Further genetic studies suggest the condition is not allelic with spinal muscular atrophy having no evidence of deletion of the survival motor neurone gene.

Positron emission tomography in imaging spinal cord tumors.

The ability of positron emission tomography (PET) to detect spinal cord tumors was studied prospectively in 14 patients presenting over a 5-year period. Abnormal uptake by [18F]-fluorodeoxyglucose (FDG) or 11C-methionine was detected in all except one. These data were assessed in relation to magnetic resonance imaging (MRI) findings with regard to tumor type and extent preoperatively, findings at operation, and subsequent clinical course. The group consisted of six astrocytomas, five ependymomas, one mixed ependymoma and astrocytoma, one schwannoma, and one ganglioglioma, all confirmed histologically. This is the largest study comparing spinal PET to MRI. Accurate preoperative correlation between PET and MRI was found in all eight patients scanned at first presentation. The PET uptake was in keeping with the low-grade histology of the tumors. Postoperatively, PET and MRI findings were in agreement in nine patients. In eight of these the findings were in keeping with the subsequent clinical course. In three patients, however, the PET findings were at variance with the clinical course and MRI findings. In one, persistent FDG uptake after radiotherapy was seen where there was subsequent tumor resolution. In two patients with low-grade astrocytomas, scanned with FDG and 11C-methionine, respectively, tracer was not taken up by residual tumor. In this small group of patients, PET did not provide additional useful information. This could be because all tumors studied were low grade and the limited spatial resolution of PET does not lend itself to imaging small spinal cord tumors. The prospective study of larger numbers of patients with a wider range of tumor types is required, but this might be difficult to achieve given the rarity of spinal cord tumors.

Audit of a children's epilepsy clinic.

A newly established tertiary epilepsy clinic at Guy's Hospital, London was evaluated using a structured questionnaire. Fifty parents of children with epilepsy completed this questionnaire, with some contribution from the children. While a high degree of satisfaction was obtained by the parents and where appropriate the children, specific questions about additional resources implied a large number of unmet needs. This raises methodological issues about the value of open-ended questions in audit questionnaires. In addition, concerns were expressed about many areas, some of which had direct medical implications that were not always raised with the doctors. It is concluded that the service has benefited from both clinical and neuropsychological support. The audit has prompted a number of improvements, including establishing a discussion group for adolescents.

Plasma amino acids in childhood epileptic encephalopathies.

Abnormalities in plasma amino acid levels have been noted in patients with various epilepsies, and sometimes also in their first degree relatives. We sought to study plasma amino acid levels in children with epileptic encephalopathies and their parents, relating findings to the pattern of cortical glucose metabolism as determined by 18fluorodeoxyglucose (FDG) positron emission tomography (PET). Twenty-eight children with cryptogenic epileptic encephalopathies were studied prospectively. Cortical glucose metabolism was evaluated by FDG PET with combined visual and semiquantitative analysis used to detect focal cortical defects. The plasma concentration of 21 amino acids in the children and their parents was measured by ion exchange chromatography and compared with control values using non-parametric statistical methods. Multivariate analysis was used to assess antiepileptic drug effects. Children were classified as: Lennox-Gastaut syndrome following infantile spasms (six patients); de-novo Lennox-Gastaut syndrome (eight); severe myoclonic epilepsy in infancy (eight) and myoclonic-astatic epilepsy (two). Four patients remained unclassified. Fourteen patients had focal/multifocal abnormalities on PET scans. The plasma level of aspartate was significantly lower in both the children with epileptic encephalopathies and in their parents (P < 0.005). The lowered aspartate levels could not be accounted for by the antiepileptic drug medication taken by the children. Further analysis showed the lowered aspartate levels to be confined to children and their parents who lacked focal PET abnormalities. These findings suggest a possible genetic abnormality in the aspartate neurotransmitter systems in the pathogenesis of seizures in the childhood epileptic encephalopathies.

Vagal nerve stimulation in epileptic encephalopathies.

OBJECTIVE: To study the effect of vagal nerve stimulation (VNS) in children with epileptic encephalopathies. METHODS AND MATERIALS: All children receiving VNS during a 2-year period at our center were studied prospectively for changes in seizure frequency, electroencephalogram (EEG), adaptive behavior, quality of life, and where appropriate, verbal/nonverbal performance. Assessments were made before and for at least 1 year after implant. RESULTS: Sixteen children were studied. One device was removed because of infection. Of the remaining 15 children, 4 had a >50% reduction and 2 had a >50% increase in seizure frequency at 1 year after implant. Median reduction in seizure frequency was 17%. There was no trend toward improvement of the EEG or adaptive behavior. Quality of life was unchanged in most areas, except in perceived treatment side effects and general behavior that were improved. In 6 children undergoing further assessment, there was a significant improvement in verbal performance; this did not correlate with reduction in seizure frequency. CONCLUSION: VNS did not significantly improve seizure frequency, severity, adaptive behavior, or the EEG during the first year of treatment for the group as a whole, although 4 children (27%) had a worthwhile reduction in seizure frequency. There were significant improvements in perceived treatment side effects and general behavior.

Neuroimaging and spectroscopy in children with epileptic encephalopathies.

AIMS: To investigate the nature of the unifocal cortical abnormalities on FDG positron emission tomography (PET) in children with an epileptic encephalopathy but no focal abnormality on electroencephalogram or standard magnetic resonance imaging (MRI). METHODS: Repeat FDG PET, surface rendered high resolution MRI, and single voxel magnetic resonance proton spectroscopy of the areas of abnormal metabolism compared to the contralateral side in 11 children aged 2 to 12 years. Imaging was repeated after a median of 13 months. RESULTS: Visual analysis of repeat FDG PET revealed similar abnormalities in 10 of 11 children. Semiquantitative analysis revealed similar sited abnormalities in eight children. One child with ictal hypermetabolism initially had an inconsistent second scan. Magnetic resonance spectra in three children showed the N-acetyl-aspartate/choline ratio was lower in the hypometabolic focus than in the reciprocal area on the opposite side, in two children it was higher, and in one child it was equal. Surface rendered MRI was normal in seven of eight children, and showed temporal lobe asymmetry in one. CONCLUSION: In children with established epileptic encephalopathies most hypometabolic areas on FDG PET are stable over time. While focal neuronal loss is likely in these areas in some children, microdysplasias or other focal cortical dysplasias are probable in others.

Inappropriate use of carbamazepine and vigabatrin in typical absence seizures.

Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.