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.

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

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.

Variability of blood-brain ratios of phenylalanine in typical patients with phenylketonuria.

Blood-brain ratios (BBR) of phenylalanine (Phe) were determined by quantitative in vivo 1H magnetic resonance spectroscopy (1H-MRS) in 17 adult patients with early-treated phenylketonuria who were randomly selected from a sample of 75 adults. Measurements were performed in all patients during steady-state conditions. The BBR showed a unimodal distribution with a mean of 4.0 (range 3.3 to 4.5). Blood-brain ratios were comparable for subgroups of patients with genotypes classified as severe, moderate, or mild and for patients on different types of diets. Brain Phe concentrations showed a strong linear correlation with blood Phe values (r = 0.93, P < 0.001). There were no saturation effects for blood Phe values up to 1.8 mmol/L, and a local regression analysis did not confirm increasing BBR for increasing blood Phe values. The intellectual outcome (Wechsler Adult Intelligence Scale) was correlated with long-term dietary control (r = -0.65, P < 0.05), fluctuation of blood Phe values during treatment (r = -0.60, P < 0.05), and concurrent blood and brain Phe concentration. The severity of white matter changes visible on magnetic resonance images (MRI) was increased with high blood and brain Phe concentrations but failed to reach statistical significance. No correlation was found between BBR values, intelligence quotient, and MRI grade. Based on the assumption that BBR show intraindividual stability, the current data do not support the hypothesis that blood-brain barrier transport of Phe is a key explanatory factor for outcome variability in the vast majority of "typical" patients with phenylketonuria.

Major and minor birth malformations and antiepileptic drugs.

In a study of infants of parents with epilepsy, malformations were twice as prevalent in these children as in controls. Children of mothers with epilepsy had more minor anomalies than those of fathers with epilepsy or controls. At 1 year of age, a greater number of minor anomalies was seen in children of mothers with epilepsy who had received treatment with antiepileptic drugs (AEDs) during pregnancy, whereas at 4 years, no difference was observed. Type of epilepsy, seizures during pregnancy, plasma levels of phenytoin or phenobarbital in the medium range, and fetal intrauterine growth did not correlate with the number of minor anomalies. We suggest that the special genetic background that predisposes to epilepsy also renders the fetus more vulnerable to major and minor anomalies. Although linkage between epilepsy and malformation is stronger than between AEDs and malformations, valproate, phenytoin, and phenobarbital show specific teratogenic effects. In addition, all AEDs unspecifically increase the number of minor anomalies. Under therapeutic conditions, valproate may be regarded as considerably teratogenic and all other observed AEDs as weakly teratogenic.

Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics.

Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons. Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine- and ethosuximide-treated mothers. This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasized. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.

Low CSF GABA concentration in children with febrile convulsions, untreated epilepsy, and meningitis.

In 14 children with epilepsy, 51 with febrile convulsions and 22 with meningitis gamma-aminobutyric acid (GABA) concentrations in lumbar CSF were determined. While the mean for CSF GABA concentrations for all epileptic children was unchanged [144 (range: 73-285) pmol/ml; controls: 148 (range: 90-243) pmol/ml] extraordinarily high GABA levels were found in the CSF of two children on valproate (525 and 557 pmol/ml) and remarkably low GABA concentrations in hitherto untreated epileptic children [109 (range: 67-176) pmol/ml]. Children with febrile convulsions [103 (range: 63-170) pmol/ml] and acute meningitis [105 (range: 65-171) pmol/ml] had significantly decreased CSF GABA concentrations (P less than 0.001 and P less than 0.02 compared with controls). The data indicate that valproate intake increases dramatically the GABA concentrations in the CSF of epileptic children. Furthermore, the study supports the concept that low GABAergic activity within the CNS may be one cause for an increased seizure frequency.

Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism.

Gamma-hydroxybutyric aciduria is a disorder of gamma-aminobutyric acid metabolism in which a compound of known neuropharmacologic activity accumulates. We have studied two patients in whom high levels of gamma-hydroxybutyric acid were found in blood, urine and cerebrospinal fluid. A coupled assay has been developed which estimates succinic semialdehyde dehydrogenase activity in isolated human lymphocytes. The mean activity of succinic semialdehyde dehydrogenase in a control and the four parents and two healthy siblings of these patients was 8.8 +/- 1.9 pmol . min-1 . mg-1 protein. In the patients the activities were 0.8 and 1.1 pmol . min-1 . mg-1 protein, approximately 9-13% of control. In the presence of saturating amounts of NAD+, lymphocyte sonicates, derived from the patients accumulated a significant amount of 14C-succinic semialdehyde from 14C-gamma aminobutyric acid, whereas none could be detected in controls. The data suggest a deficiency of succinic semialdehyde dehydrogenase in these patients, the first documented defect of the metabolism of gamma-aminobutyric acid in man.

Measurement of fatty acid oxidation in premature newborn infants with the 13C-triolein breath test.

The 13C-triolein breath test is a method giving evidence of extent and rate of fatty acid oxidation in newborn infants on parenteral nutrition. The test has the special advantage of being non-invasive. Triolein labeled with the stable carbon isotope 13C and emulsified in soybean-oil is used as a tracer. 10 mg of 13C triolein per kg body weight are administered intravenously. The 13CO2 resulting from the fatty acid oxidation is analysed in expired breath by ratio-mass-spectrometry. The calculated 13C elimination is representative of the rate of fatty acid oxidation during the examination period. First studies on 15 premature infants have shown that an average of 27.0 +/- 1.8% of the dose administered is oxidized within 4 h. The present results suggest that the oxidation rate may be related to the maturity of the prematurely born infants.

The prognostic value of EEG patterns in epilepsies with infantile spasms.

By scoring EEG patterns (hypsarrhythmia = 10, absence of sleeping patterns = 10, focal epileptic discharge = 5, general-treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EEG did not have any ending ACTH therapy free of seizures showed lower scores compared to those infants relapsing after the end of ACTH treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EED did not have any prognostic significance. Using EEG scores it might be possible to separate non-responders and responders after 3 weeks of ACTH therapy, thus shortening ACTH treatment in non-responding infants.

13C-ethanol and 13C-acetate breath tests in normal and aldehyde dehydrogenase deficient individuals.

Four normal and five aldehyde dehydrogenase (ALDH) isozyme I deficient individuals were subsequently loaded with (1-13C)ethanol and (1-13C)sodium acetate and the conversion of the label to 13CO2 was determined in expired air by isotope ratio mass spectrometry. In the 13C-acetate breath test, both groups showed virtually identical recovery of the label in expired air, namely 48.5 +/- 2.3% (mean +/- S.D.) for normal and 46.8 +/- 5.7% for deficient individuals. However, in the 13C-ethanol breath test, both the groups performed differently. On average, although a certain overlap of the single data was observed, the recovery of the label after four hours was 43.4 +/- 3.8% for the normal and 35.6 +/- 6.8% for the ALDH deficient subjects. These findings suggest a slower conversion of ethanol to carbon dioxide in aldehyde dehydrogenase deficient individuals, which may be another consequence of this deficiency besides the higher plasma acetaldehyde levels observed after ethanol loading in comparison to individuals with normal aldehyde dehydrogenase activity.

Treatment in typical and atypical rolandic epilepsy.

Benign rolandic epilepsy is the most common epilepsy of childhood. Regarding seizure control typical and atypical rolandic epilepsies have a reasonable prognosis. In a recent prospective study STM was shown to control seizures in BECTS and STM is regarded as first line drug for this epilepsy in countries having access to this drug. Otherwise, CBZ is used most often and very effectively in BECTS. However, CBZ has the disadvantage to worsen clinical and EEG features up to the precipitation of CSWS in few patients. Epileptic seizures are often not the main problem in atypical rolandic epilepsies like CSWS or LKS and the amelioration of cognitive dysfunction by epileptic discharge is the prominent aim of an AED therapy. Steroids seem the have the best efficacy in these cases.

[Selective screening for amino and organic acid inborn errors]. / Selektives Screening auf Amino- und Organoazidopathien.

Aminoacidopathies and organoacidopathies are the most common acute life-threatening inborn errors of metabolism in the neonatal period. In the Federal Republic of Germany approximately 1 out of 5000 newborns is currently diagnosed as having an aminoacidopathy and approximately 1 out of 9000 newborns an organoacidopathy. Especially in the case of organoacidopathies there is substantial evidence that this number represents an underestimation. Many cases of amino- and organoacidopathies are still likely to remain undiagnosed. The incidence figures would warrant neonatal population screening for these disorders; however, the complexity and expense of the current methods prohibit this approach. Instead specialized investigations are carried out in children who develop symptoms indicative of an inborn error of metabolism. This approach is called selective screening. Early diagnosis, therefore, rests on a high degree of suspicion. In this paper clinical and laboratory findings of amino- and organoacidopathies are summarized. They can be nonspecific and misinterpreted. In the neonate and infant the presentation is commonly that of an acute overwhelming disease, whereas in the older child unexplained mental and/or neurological problems are often the leading symptom. We present an algorithm for the quick and comprehensive diagnosis of acutely presenting inborn errors of metabolism using commonly available parameters. However, in many cases the definitive diagnosis is not reached by selective metabolic screening of a single urine specimen of a patient, but requires close cooperation between the referring physician and the metabolic specialist. Multiple analyses, sometimes of different physiological fluids, or even in vivo and in vitro loading tests may be necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cerebral tuberous sclerosis and Coats disease]. / Tuberöse Hirnsklerose und Morbus Coats.

A 10-year-old boy with known tuberous sclerosis since early childhood suffered from unilateral Coats' disease. Initially his parents noticed a divergent squint. On examination, well-advanced Coats' disease involving almost the entire retina including the macula was found. Visual acuity had decreased to 20/300. Intrascleral diathermy was successfully performed, and after painful secondary glaucoma, cryotherapy of the ciliary body became necessary. Coats' disease has been reported in a number of genetic diseases, most of them quite variable in their clinical manifestations. To the best of our knowledge this is the first description of Coats' disease associated with tuberous sclerosis, which is known to be of genetic origin. Although in Coats' disease no genetic predisposition has been proven to date, the growing list of genetic diseases associated with Coats' disease should be considered in patients presenting with this retinopathy.

[Sleep modifies anticholinergic mydriasis]. / Schlaf beeinträchtigt die anticholinerge Mydriasis.

In sleep, the eyelids are closed and the pupils narrow. The pupil width indicates alertness and, if it is narrow, sleepiness. The deeper the sleep, the narrower the pupil: miosis during drowsiness, sleep, sedation and general anesthesia relies on reduced inhibition of the oculomotor nucleus and, even more, on reduced sympathetic tone (it is as sympatholysis that accounts for the miosis exerted by the famous "cocktail lytique" onto an iris whose sphincter is weakened from briskly elevated IOP in angle-closure glaucoma). For whatever reason a lack of sympathetic tone occurs, a poor response to anticholinergic mydriatics will be the consequence. This communication is concerned with children who received tropicamide, cyclopentolate or atropine for diagnostic pupil dilation and cycloplegia but, during subsequent sleep, exhibited an unsatisfactory mydriatic response that could be overcome by additional administration of phenylephrine. Thus, parasympatholytic mydriasis can be proven to be a function of the sympathetic tone. The pupil shrinks during deep sleep even after atropine. If the conditions of deep sleep, sedation or general anesthesia are present and mydriasis needs to be maintained, an additional administration of a sympathomimetic compound is mandatory.

[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.

Clinical and electro-clinical classification of epileptic seizure in west Uganda.

When compared to that of industralised countries, the prevalence of epilepsy in developing countries has generally been found to be higher and in some areas extremely high rates of up to 57 cases per 1000 inhabitants have been reported. The reasons for this difference are still widely unknown and detailed epidemiological as well as clinical data are scarce, especially from rural Africa. The present study was conducted in western Uganda, in an area of high epilepsy prevalence, known to be endemic for onchocerciasis. The seizures of all 91 epilepsy patients diagnosed in this area over the period of two years were classified according to the criteria of the International League against Epilepsy. Based on seizure description alone, the predominant seizure was classified as generalised in 57 patients (63%), as partial in 22 (24%) and unclassified in 12 (13%). An EEG record was analysed in 55 out of 91 patients, showing focal epileptiform activity (EA) in 12, multifocal EA in 9 and primarily generalised EA in 6 patients. When in addition to clinical information, the EEG results in the 27 patients with EA were taken in consideration for seizure classification, the proportion of partial seizures increased to 78% (n = 21); inversely the proportion of generalised seizures fell to 22% (n = 6). The predominance of partial seizures would be compatible with a localised brain lesion as a frequent cause for epileptic seizures in the study area. The findings further corroborate recent observations from several African countries of an association between epilepsy and onchocerciasis.