The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy.

We present four children, three of them boys, affected with an identical clinical pattern consisting of early-onset ataxia, delayed dentition, hypomyelination and cerebellar atrophy. Dental radiographs showed variable absence of succedaneous teeth. Proton MR spectroscopy in one child showed elevated white matter myo-inositol. As the clinical and radiological picture in these patients is identical to that of four cases described earlier, we suggest that this disorder with ataxia, delayed dentition and hypomyelination (ADDH) represents a new entity. With the characteristic tooth abnormalities it should be straightforward to identify new patients in order to facilitate the search for the underlying genetic defect.

Combined EEG and MEG analysis of early somatosensory evoked activity in children and adolescents with focal epilepsies.

OBJECTIVE: The study aimed to evaluate differences between EEG and MEG analysis of early somatosensory evoked activity in patients with focal epilepsies in localizing eloquent areas of the somatosensory cortex. METHODS: Twenty-five patients (12 male, 13 female; age 4-25 years, mean 11.7 years) were included. Syndromes were classified as symptomatic in 17, idiopathic in 2 and cryptogenic in 6 cases. 10 patients presented with malformations of cortical development (MCD). 122 channel MEG and simultaneous 33-channel EEG were recorded during tactile stimulation of the thumb (sampling rate 769 Hz, band-pass 0.3-260 Hz). Forty-four hemispheres were analyzed. Hemispheres were classified as type I: normal (15), II: central structural lesion (16), III: no lesion, but central epileptic discharges (ED, 8), IV: lesion or ED outside the central region (5). Analysis of both sides including one normal and one type II or III hemisphere was possible in 15 patients. Recordings were repeated in 18 hemispheres overall. Averaged data segments were filtered (10-250 Hz) and analyzed off-line with BESA. Latencies and amplitudes of N20 and P30 were analyzed. A regional source was fitted for localizing S1 by MRI co-registration. Orientation of EEG N20 was calculated from a single dipole model. RESULTS: EEG and MEG lead to comparable good results in all normal hemispheres. Only EEG detected N20/P30 in 3 hemispheres of types II/III while MEG showed no signal. N20 dipoles had a more radial orientation in these cases. MEG added information in one hemisphere, when EEG source analysis of a clear N20 was not possible because of a low signal-to-noise ratio. Overall N20 dipoles had a more radial orientation in type II when compared to type I hemispheres (p=0.01). Further N20/P30 parameters (amplitudes, latencies, localization related to central sulcus) showed no significant differences between affected and normal hemispheres. Early somatosensory evoked activity was preserved within the visible lesion in 5 of the 10 patients with MCD. CONCLUSIONS: MEG should be combined with EEG when analyzing tactile evoked activities in hemispheres with a central structural lesion or ED focus. SIGNIFICANCE: At time, MEG analysis is frequently applied without simultaneous EEG. Our results clearly show that EEG may be superior under specific circumstances and combination is necessary when analyzing activity from anatomically altered cortex.

Cardiorespiratory regulation in migraine. Results in children and adolescents and review of the literature.

To investigate autonomic regulation in juvenile migraine we studied 70 children and adolescents with migraine during the headache-free period and 81 healthy controls by cardiorespiratory function tests. Heart rate variability was analysed with time and frequency domain indices during spontaneous breathing at rest and during metronomic breathing. Changes of heart rate and blood pressure were studied during tilt-table test, active standing, Valsalva manoeuvre and sustained handgrip. We found significant differences in metronomic breathing, tilt-table test and Valsalva manoeuvre. We interpret our findings and results reported in the literature as pointing to a restricted ability of the system to rest, which supports therapies intending to further this ability. In autonomic tests, hyperreactivity in juvenile migraineurs changes to hyporeactivity and passive coping in adults. This might be explained by disturbances of raphe nuclei and the periaqueductal grey. It corresponds to psychological findings in juvenile migraineurs reporting hypersensitivity and repressed aggression and claiming learned helplessness.

Intraoperative MRI for interventional neurosurgical procedures and tumor resection control in children.

INTRODUCTION: Despite the introduction of neuronavigational systems, radical tumor removal is still problematic in many neurosurgical procedures. Thus, direct intraoperative imaging for tumor resection control was implemented with an intraoperative magnetic resonance imaging (ioMRI) scanner installed in the operating room. Whereas most procedures with ioMRI were carried out in adults, we summarize 7 years of experience using ioMRI in children for interventional neurosurgical procedures or for tumor resection control. METHOD: An open magnetic resonance scanner (Magnetom Open 0.2 T) was installed in the neurosurgical operating room. For tumor resection control, ioMRI was performed in 35 procedures. After the ioMRI scans were analyzed with respect to quality, the identification of residual tumor was considered by the attending neuroradiologist and neurosurgeon. If residual tumor tissue was present, a new three-dimensional (3D) dataset was acquired to update the neuronavigation; subsequently, the tumor resection was extended. In all these procedures, the results of the ioMRI were checked by an early postoperative high-field magnetic resonance imaging (MRI) study. In addition, ioMRI was carried out in ten other children to monitor interventional neurosurgical procedures. RESULTS: In all children, ioMRI was adequate both for tumor resection control and monitoring of interventional procedures. Primary radical removal of tumor was reached in 40% as confirmed by ioMRI, but in 60% of the patients, the tumor resection procedure was extended after residual tumor was detected using the new 3D dataset for navigational update. By using ioMRI, radical tumor removal improved up to 83% as confirmed by early postoperative MRI. Procedure-related complications were not seen in our series. For all MR-guided biopsies, histology findings could be confirmed, and aspiration of intracranial cysts or abscesses could be monitored online. CONCLUSION: IoMRI using the open magnetom is suitable for detecting residual tumor tissue, can compensate for the phenomenon of brain shift using a new intraopertive 3D dataset for extended tumor resection, and is capable of monitoring interventional neurosurgical procedures. By using ioMRI for tumor resection control, the degree of tumor resection could be significantly improved.

Glucose and leucine kinetics in idiopathic ketotic hypoglycaemia.

AIMS: To investigate glucose and leucine kinetics in association with metabolic and endocrine investigations in children with ketotic hypoglycaemia (KH) in order to elucidate the underlying pathophysiology. METHODS: Prospective interventional study using stable isotope tracer in nine children (mean age 4.23 years, range 0.9-9.8 years; seven males) with KH and 11 controls (mean age 4.57 years, range 0.16-12.3 years; four males). RESULTS: Plasma insulin levels were significantly lower in KH compared to subjects in the non-KH group. Plasma ketone body levels were significantly higher in KH than in non-KH. Basal metabolic rate was significantly higher in subjects with KH (45.48+/-7.41 v 31.81+/-6.72 kcal/kg/day) but the respiratory quotients were similar in both groups (KH v non-KH, 0.84+/-0.05 v 0.8+/-0.04. Leucine oxidation rates were significantly lower in children with KH (12.25+/-6.25 v 31.96+/-8.59 micromol/kg/h). Hepatic glucose production rates were also significantly lower in KH (3.84+/-0.46 v 6.6+/-0.59 mg/kg/min). CONCLUSIONS: KH is caused by a failure to sustain hepatic glucose production rather than by increased glucose oxidation rates. Energy demand is significantly increased, whereas leucine oxidation is reduced.

Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults.

Focal cortical dysplasias (FCD) are defined as circumscribed malformations of cortical development. They result from an impairment of neuronal proliferation, migration and differentiation. In the diagnosis of focal epilepsy FCD prevalence ranges between 5% and 25%, depending on patient collective and imaging techniques. Several 'cryptogenic' epilepsies may be caused by FCD but have not been diagnosed because of the lack of high-quality magnetic resonance imaging assessment. Retrospective analysis of patients who have undergone epilepsy surgery can be biased because of the fact that they represent a mere subset of potential FCD diagnoses. Epilepsy typically manifests within the first years of life, but has been documented up to the age of 60 years. Cognitive impairment commonly accompanies early onset. Epilepsy is often refractory to antiepileptic drug (AED) treatment. Clinical observations and pathophysiological findings illustrate intrinsic epileptogenicity. Upregulation of drug transporter proteins has been found in FCD tissue. There is no specific drug treatment in FCD, as any AED used in focal epilepsy could prove effective. A sequential AED therapy should be designed individually and take side effects as well as developmental progresses into consideration. Fifty to sixty-five percent of FCD patients are rendered seizure-free after surgery. Presurgical evaluation should be initiated after two unsuccessful AED trials. Both risks and potential benefits regarding seizure control and developmental impairment need to be considered on an individual basis when deciding between surgical intervention and conservative treatment. Current knowledge on epilepsy course and psychomotor development in FCD is limited in the absence of qualified long-term studies combining imaging with cognitive evaluation.

[Optimizing epilepsy therapy in children and adolescents with lamotrigine]. / Optimierung der Epilepsietherapie von Kindern und Jugendlichen mit Lamotrigin.

Lamotrigine is a broadly effective antiepileptic drug in mono- and add-on therapy for children and adolescents with focal and generalized epilepsies. Some epileptologists consider lamotrigine as the drug of primary choice in older school children and adolescents because of its good tolerability (no increase of body weight, no impairment of cognitive functions, due to new data probably no teratogenic properties). Lamotrigine can be used with good efficacy in numerable epilepsy diseases, such as tuberous sclerosis, juvenile neuronal lipofuscinosis and Rett syndrome. The first studies show that lamotrigine is also effective in children under 2 years of age. For therapy of difficult-to-treat epilepsies the combination of lamotrigine with valproate has proved as especially useful. This clinical observation is supported by new results of animal experiments. The dose-dependant and typical CNS side effects vertigo, ataxia, nausea, tremor and diplopia are found most frequently. The rate of allergic skin rashes which was very high before 1998 has decreased markedly by new dosage guidelines and is now as low as in older antiepileptic drugs. Lamotrigine does not impair cognitive functions, especially not memory and language. It has mood-stabilizing features and may improve quality of life. In animal experiments lamotrigine shows antiepileptogenic and neuroprotective effects.

Leukoencephalopathy with ataxia, hypodontia, and hypomyelination.

The authors describe four unrelated girls with a distinctive neurologic disorder with early-onset progressive ataxia and hypodontia with a characteristic pattern of delayed dentition. Cerebral MRI shows hypomyelinated white matter and cerebellar atrophy; 1H-MRS of white matter reveals a marked elevation of myo-inositol.

Sedation with 4-hydroxybutyric acid: a potential pitfall in the diagnosis of SSADH deficiency.

Deficiency of succinic semialdehyde dehydrogenase (SSADH) is a rare neurometabolic disorder with accumulation of 4-hydroxybutyric acid (4-HBA) as a biochemical hallmark. We present a boy with an unresolved severe neurological disorder and intermittent elevation of 4-HBA in serum and CSF which was later shown to result from iatrogenic administration of 4-HBA for sedation purposes.

Impact of location on outcome in children with low-grade oligodendroglioma.

BACKGROUND: Childhood low-grade oligodendroglioma (WHO grade II) are rare. No controlled pediatric study has been published, to generate high level evidence for the best treatment. Therefore, we retrospectively analyzed data available from pediatric patients. PROCEDURE: We pooled data from two prospective German multicentre studies (HIT-DOK and HIT-LGG). Eligibility criteria were: (1) primary neoplasm, (2) histology of pure oligodendroglioma WHO grade II, (3) intracranial location, (4) age <18 years, (5) date of diagnosis: 1990-2002, (6) observation time >6 months. The outcome was analyzed by using the SPSS-software. RESULTS: Nineteen boys and 13 girls were eligible (median age 10.3 years). The tumor locations included: 26 peripheral tumors (23 cerebral hemisphere, 3 cerebellum), and 6 central tumors (4 thalamus, 1 frontal mesencephalon, 1 basal ganglia). Resections were classified as complete in 18 (14 cerebral hemispheres, 3 cerebellum, 1 thalamus) and less than complete in 14 patients (3 subtotal resections, 8 partial resections, 3 biopsy). The 5-year event-free survival (EFS) and overall survival (OS) rates of all patients were 81.3 and 84.4%, respectively (median observation time 3.8 years). All of the 26 children with peripheral tumors were alive with no tumor progression, but five of six patients with central tumors died of disease (median time to death 1.6 years). This survival difference was statistically significant for EFS (P < 0.0001) and OS (P < 0.0001). The difference between completely resected versus incompletely resected tumors was far less striking (P > 0.06). CONCLUSIONS: The outcome of children with centrally located low-grade oligodendroglioma is particularly poor, while tumors of the cerebral hemispheres and cerebellum carry an excellent prognosis, even with minor tumor resection.

Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF.

BACKGROUND: Two unrelated girls had early onset of nystagmus and epilepsy, absent psychomotor development, and almost complete absence of myelin on cerebral MRI. The clinical features and MR images of both patients resembled the connatal form of Pelizaeus-Merzbacher disease (PMD), which is an X-linked recessive disorder caused by duplications or mutations of the proteolipid protein gene (PLP). OBJECTIVE: To define a unique neurometabolic disorder with failure of myelination. METHOD: S AND RESULTS: 1H-NMR of CSF in both girls was performed repeatedly, and both showed highly elevated concentrations of N-acetylaspartylglutamate (NAAG). The coding sequence of the gene coding for glutamate carboxypeptidase II, which converts NAAG to N-acetylaspartate (NAA) and glutamate, was entirely sequenced but revealed no mutations. Even though both patients are girls, the authors sequenced the PLP gene and found no abnormality. CONCLUSIONS: NAAG is an abundant peptide neurotransmitter whose exact role is unclear. NAAG is implicated in two cases of unresolved severe CNS disorder. Its elevated concentration in CSF may be the biochemical hallmark for a novel neurometabolic disorder. The cause of its accumulation is still unclear.

New pattern of brain MRI lesions in isolated complex I deficiency.

We describe a boy presenting at the end of the first year of life with severely delayed motor development and only mild mental retardation. Neurological examination revealed axial hypotonia, mild ataxia and pyramidal signs. Elevated lactate and protein in cerebrospinal fluid were the most prominent laboratory abnormalities. Brain MRI showed severe supratentorial white matter changes. Cerebellar white matter appeared normal whereas the signal of the atrophic cerebellar cortex was markedly increased. In vivo 1H-magnetic resonance spectroscopy of the parietooccipital white matter region showed a distinct resonance of lactate. By means of biochemical analysis of respiratory chain enzymes in fibroblasts, the diagnosis of an isolated complex I deficiency could be established in our patient.

Ultrasound findings in follow-up investigations in a case of aspartoacylase deficiency (canavan disease).

Aspartoacylase deficiency is a neurodegenerative disease which typically starts in the first months of life with muscular hypotonia and developmental standstill. One of the first diagnostic procedures in this situation is an ultrasound of the brain. There is little information available about sonographic changes in Canavan disease. We present for the first time an ultrasound follow-up in a proven case of aspartoacylase deficiency from 3 weeks to 22 months. High echogenicity of the white matter was present in the neonatal period. Additional sonographic phenomena resulting in a characteristic pattern were shown in further investigations. The distinctive sonomorphology is compared to a few other cases in the literature. The correlation to the neuropathological course of the white matter changes is discussed. Recognition of the sonographic features in addition to the clinical presentation may contribute to an effective biochemical work-up.

Measurement of gastric emptying by 13C-octanoic acid breath test versus scintigraphy in diabetics.

In this prospective study, we compared the assessment of gastric emptying by the 13C-octanoic acid breath test to gastric emptying scintigraphy in diabetics. We also examined the relationship between gastric emptying parameters and gastric symptoms and cardiovascular autonomic function. The 13C-octanoic acid breath test and scintigraphy were performed simultaneously in 24 diabetics with a solid test meal (1 egg, doubly labelled with 91 mg 13C-octanoic acid and 50 MBq 99mTechnetium-Nanocoll, 60 g white bread, 5 g margarine and 150 ml water). At fifteen-minute intervals, breath samples were taken over 4 hours and examined by mass spectrometry. In parallel, scintigraphy was performed for 2 hours at one minute intervals. Using breath test data, gastric emptying half time (t (1/2) ), lag-phase (t lag ) and gastric emptying coefficient (GEC) were calculated. Subsequently, the correlation of these results with the equivalent data from scintigraphy were determined employing a regression method. To detect a cardiovascular autonomic neuropathy, a 24-h ECG recording was performed. The prevalence of gastrointestinal symptoms in our collective was assessed by a standardized questionnaire. There was a highly significant positive correlation of both 13C-octanoic acid breath test t (1/2) and scintigraphic t (1/2) (r = 0.8257; p < 0.0001) and 13C-octanoic acid breath test t lag and scintigraphic t lag (r = 0.6302; p < 0.001). The sensitivity of the 13C-octanoic acid breath test was 1 and the specificity was 0.73. In our study, there was no significant association of cardiovascular and gastrointestinal autonomic neuropathy. Furthermore, there was no significant relationship between the prevalence of gastrointestinal symptoms and gastric emptying disorders. We conclude that the 13C-octanoic acid breath test represents a suitable method to measure disordered gastric emptying in diabetics due to its highly significant positive correlation to scintigraphy and due to its validity. It is not possible to predict diabetic gastroparesis on the basis of other autonomic function disorders or because of dyspeptic symptoms.

[Pigmented retinopathy as a presenting sign of mitochondrial encephalomyopathy without external ophthalmoplegia]. / Retinopathie als Leitbefund einer Mitochondriopathie ohne externe Ophthalmoplegie. Bedeutung einer mtDNA-Mutationsanalyse auch bei untypischer Befundkonstellation.

BACKGROUND: Mitochondrial encephalomyopathies result from deletions in the nuclear or mitochondrial (mt) DNA. Deletions in the mtDNA are often sporadic. Mitochondriopathies are commonly associated with chronic progessive external ophthalmoplegia (CPEO). Here we describe a patient with a structural mtDNA aberration whose presenting sign was impaired visual acuity in the presence of a pigmented retinopathy but lack of impaired ocular motility. PATIENT: A 7-year-old girl presented with impaired visual acuity (0.4 OD and 0.5 OS), coarse hyperpigmentation of the posterior pole and diffuse hyperpigmentation with irregular depigmentation in the periphery. Scotopic and photopic as well as multifocal ERG were abnormal. Further symptoms included an incomplete inner ear deafness, ataxia, lapses of coordination and an intention tremor. Compared with her twin sister, the patient's speech was less modulated and slower. MRI scanning disclosed symmetric changes of density in the basal ganglia and nucleus dentatus as well as in the brainstem. ECG yielded no evidence of an AV-node block. Molecular biological analysis showed a structural rearrangement of the mtDNA. CONCLUSIONS: Mitochondrial encephalomyopathies in early ages may present with pronounced retinal changes in the absence of external ophthalmoplegia.Therefore, it appears prudent to include a neuropediatric evaluation as well as a mutation screening of the mtDNA in the evaluation of pediatric patients with diffuse non-specific pigmented retinopathies.

Treatment of paediatric pontine glioma with oral trophosphamide and etoposide.

To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg x m(-2) x day(-1) combined with oral etoposide at 25 mg x m(-2) x day(-1) starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies.

Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation.

Guanidinoacetate methyltransferase (GAMT) deficiency (McKusick 601240), an inborn error of creatine biosynthesis, is characterized by creatine depletion and accumulation of guanidinoacetate (GAA) in the brain. Treatment by oral creatine supplementation had no effect on the intractable seizures. Based on the possible role of GAA as an epileptogenic agent, we evaluated a dietary treatment with arginine restriction and ornithine supplementation in order to achieve reduction of GAA. In an 8-year-old Kurdish girl with GAMT deficiency arginine intake was restricted to 15 mg/kg/day (0.4 g natural protein/kg/day) and ornithine was supplemented with 100 mg/kg/day over a period of 14 months. The diet was enriched with 0.4 g/kg/day of arginine-free essential amino acid mixture and creatine treatment remained unchanged (1.1 g/kg/day). Guanidino compounds in blood, urine, and CSF were measured by means of cation-exchange chromatography. The combination of arginine restriction and ornithine supplementation led to a substantial and permanent decrease of arginine without disturbance of nitrogen detoxification. Formation of GAA was effectively reduced after 4 weeks of treatment and sustained thereafter. Biochemical effects were accompanied by a marked clinical improvement. Distinctly reduced epileptogenic activities in electroencephalography accompanied by almost complete disappearance of seizures demonstrates the positive effect of GAA reduction. This indicates for the first time that GAA may exert an important epileptogenic potential in man. Arginine restriction in combination with ornithine supplementation represents a new and rationale therapeutic approach in GAMT deficiency.