Nonconvulsive status epilepticus--a possible cause of mental retardation in patients with Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is one of the most severe types of childhood epilepsy. It is usually resistant to treatment and associated with mental retardation. To delineate the risk factors associated with the outcome of LGS, we evaluated, in a retrospective and multicentre study, the course of the disease, EEG tracings, and intellectual function in 101 patients. Inclusion criteria were the presence of tonic seizures as well as slow spike and wave complexes in the EEG. The average documented observation period was 16 years (range 4-31 years). Overall, the intellectual and neurological outcome was poor. At the last follow-up, 38% of the patients could not speak, 21% were unable to walk and only 4% were free of seizures. Four independent risk factors for severe mental retardation were identified by multivariate analysis. These were in a decreasing order of importance: nonconvulsive status epilepticus (NCSE), odds ratio (OR) 25.2, a previous diagnosis of West syndrome (OR 11.6), a symptomatic etiology of epilepsy (OR 9.5), and an early age at onset of epilepsy (OR 4.7). The results highlight the association between NCSE and the severity of mental retardation in patients with LGS; this association appears to be independent of symptomatic etiology. Our data provide an indirect evidence that, at least in some of the patients, NCSE is not only a concomitant feature, but also a cause of severe mental retardation.

Temporary pure red-cell aplasia during valproate monotherapy: clinical observations and spectral electroencephalographic aspects.

We report the case of a 4-year-old boy with pure red-cell aplasia associated with sodium valproate monotherapy. Treatment with valproate was initiated because of idiopathic tonic-clonic seizures; he became free of seizures. During the introduction of and ongoing antiepileptic drug treatment, clinical and laboratory controls using electroencephalographic (EEG) spectral analysis were performed at regular intervals and disclosed normal values. Ten months after the introduction of valproate, clinical examination was normal except for marked pallor. Peripheral blood showed macrocytic anemia and the bone marrow finding was isolated absolute erythroblastopenia. At the same time, significant changes in EEG background activity were present as well-defined slowing. There was an increase in the relative power of theta activity and a decrease in alpha 2 activity in the occipital regions. Valproate was discontinued and phenobarbital therapy introduced. A complete resolution of the hematologic damage was observed after valproate withdrawal. Recovery of the hematologic parameters started 14 days after discontinuation of valproate therapy, while normalization of EEG background activity was observed earlier. The patient maintained stable hematologic values and seizure control without disturbances of the spectral EEG. After 6 months of phenobarbital therapy, re-administration of sodium valproate was not followed by recurrence of any clinical or electrophysiologic symptoms or abnormalities.

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.

Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis.

Familial hemiplegic migraine is a rare autosomal dominant disorder associated with stereotypic neurologic aura phenomena including hemiparesis. So far two chromosomal loci have been identified. Families linked to the chromosome 19 locus display missense mutations within the CACNL1A4 gene. Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, we hypothesize that a dysfunction of the mutated calcium channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients.

Neuropsychological and biochemical investigations in heterozygotes for phenylketonuria during ingestion of high dose aspartame (a sweetener containing phenylalanine).

Aspartame, a high intensity sweetener, is used extensively worldwide in over 5,000 products. Upon ingestion, aspartame is completely metabolized to two amino acids and methanol (approximately 50% phenylalanine, 40% aspartic acid, and 10% methanol). The effects of aspartame on cognitive function, electroencephalograms (EEGs) and biochemical parameters were evaluated in 48 adult (21 men, 27 women) heterozygotes for phenylketonuria (PKUH), PKUH subjects whose carrier status had been proven by DNA analysis ingested aspartame (either 15 or 45 mg/kg/day) and placebo for 12 weeks on each treatment using a randomized, double-blind, placebo-controlled, crossover study. A computerized battery of neuropsychological tests was administered at baseline weeks -2 and -1, and during treatment at weeks 6, 12, 18, and 24. Samples for plasma amino acids and urinary organic acids were also collected during these visits. EEGs were evaluated by conventional and spectral analysis at baseline week -1 and treatment weeks 12 and 24. The results of the neuropsychological tests demonstrated that aspartame had no effect on cognitive function. Plasma phenylalanine significantly increased, within the normal range for PKUH, at 1 and 3 h following the morning dose of aspartame in the group receiving the 45 mg/kg per day dose only. There were no significant differences in the conventional or spectral EEG analyses, urinary organic acid concentrations, and adverse experiences when aspartame was compared with placebo. This study reaffirms the safety of aspartame in PKUH and refutes the speculation that aspartame affects cognitive performance, EEGs, and urinary organic acids.

GM2D gangliosidosis B1 variant in a boy of German/Hungarian descent.

After the introduction of 4-methylumbelliferyl-2-acetamido-2-deoxy-beta A-D-glucopyranoside (4MUG) and its sulfated form (4MUGS) in the pre- and postnatal diagnosis and carrier identification of gangliosidosis genotypes, infrequent forms of the GM2 gangliosidosis Type B (Tay-Sachs disease) have been observed which show normal activity of Hexosaminidase A (Hex A) isoenzyme with the substrate 4MUG but absent or deficient activity against the sulfated form 4MUGS. Here we report the observation of a German/Hungarian boy aged 12 when he died with a prolonged course of a neurodegenerative disorder, later biochemically identified as a GM2 gangliosidosis B1-variant which is characterized by a deficient Hex A activity only against 4MUGS. The first clinical symptoms had occurred after the age of 14 months with a clear manifestation of the disease at age 3, when he presented disturbances of movement and tended to fall down. The slowly progressive course with brain atrophy, seizures and severe mental deterioration resulted in death after almost 9 years. At autopsy, the typical light microscopic neuronal changes of a "lysosomal storage disorder" were found, with multilamellar concentric bodies (MCB) and Zebra bodies in the neuronal cytoplasm at the electron microscopic level.

Treatment of infantile spasms with high-dosage vitamin B6.

High-dose vitamin B6 (pyridoxine-HCl, 300 mg/kg/day orally) was introduced as the initial treatment of recently manifested infantile spasms in 17 children (13 symptomatic cases with identified brain lesion and 4 cryptogenic cases). 5 of 17 children (2 cryptogenic, 2 with severe pre/perinatal brain damage and one with Sturge-Weber syndrome) were classified as responders to high-dose vitamin B6. In all 5 cases the response to vitamin B6 occurred within the first 2 weeks of treatment and within 4 weeks all patients were free of seizures. Two patients developed other seizures (partial seizures, etiologically unclear blinking attacks), but no relapse of infantile spasms was observed among the five responders to vitamin B6. No serious adverse reactions were noted. Side effects were mainly gastrointestinal symptoms, which were reversible after reduction of the dosage. Considering the life-threatening side effects of treatment with ACTH/corticosteroids or valproate, a controlled clinical trial with high-dose vitamin B6 would appear justified to either prove or disprove efficacy.

Involvement of the central nervous system in renal hypertension.

Involvement of the central nervous system (CNS) is a major complication of renal hypertension and is usually due to hypertensive encephalopathy. During a 17-year period we observed 25 children with renal hypertension associated with CNS manifestations in the absence of (group A) and 33 in the presence of advanced renal failure (group B). Convulsions were the most important symptom (65% in both groups combined). Other manifestations were reduced consciousness (69%), visual disturbances (28%), hemiplegia (14%), and cranial nerve palsy (10%). In 56% of children in group A, hypertension was recognised only after appearance of CNS symptoms. Three patients in group A and 19 in group B died. Intracranial haemorrhage associated with hemiplegia was found in 3 cases. From 1970-1977 to 1978-1986 the number of patients and the mortality in group B declined dramatically, probably as a result of improved antihypertensive and renal replacement therapy. In contrast, in group A the number of patients and of CNS symptoms remained similar. The study underlines the importance of frequent blood pressure monitoring in presence of acute or chronic renal disease.

Comparison of the EEG background activity of epileptic children and children with migraine.

The EEG background activity was investigated in the interictal EEGs of 19 children with migraine and of 88 patients with epilepsy of idiopathic origin in the third year of treatment. The control group consisted of 96 healthy children matched for age. Spectral analysis was performed, and parameters of the relative power within the conventional frequency bands were compared with norm data. The means of parameters representing the background activity of migraine as well as of epileptic patients significantly differed (slowing) from those of healthy controls. No significant differences were found between the main groups of migraine and epileptic patients. In comparing the subgroups of epileptic as well as of migraine patients, the composition of the background activity in migraine patients without aura differed the least from the controls. While the background activity in epileptics (especially those with an unfavourable course) showed a moderate slowing, a high degree of slowing was observed in patients with migraine accompagnée.

EEG development in early treated PKU patients from birth to 6 years of age.

In 126 early treated PKU patients (type I and type II) a close EEG follow up was performed from birth up to 6 years of age. A total of 1465 EEGs were performed before and after onset of dietary treatment and on 11 more subsequent occasions. The composition of the background activity was normal up to 6 years when only a small number of the children (19) showed no dominant alpha activity. The frequency of epileptiform activity of generalised as well as focal type was low in the first 2 years of life, but afterwards slightly enhanced in comparison to normal control groups. Other findings like generalised theta paroxysms or focal slow waves were rarely observed. Under a standardised protein load at 6 months (52 patients) and at 5 years of age (42 patients) a moderate generalised slowing of the background activity but no other abnormalities were noted.

Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early.

In 34 children with phenylketonuria (PKU) treated early the prognostic value of the age on institution of the diet (within the first 3 months of life) and of the quality of dietary treatment was determined in two different ways: 1) following intelligence closely (IQ) and (2) evaluating the EEG development up to their 12th (n = 34) and 15th (n = 18) years of life as appropriate. In general, IQ scores were found to be normal from the 4th-15th years of life. In our group of patients there was no effect on the IQ of the timing of diet onset. Children with "strict" dietary control showed a significantly higher IQ than those with "loose" control. One hundred and fifty-four EEGs (10/20 system, awake with eyes closed) were recorded at intervals of 2 years and conventionally evaluated. The development of alpha-activity was found to be normal. Beta-activity was enhanced. Abnormal EEG findings like general slowing and generalized paroxysmal activity (GPA) with or without spikes were more frequent in children with PKU than in controls, with the exception of focal abnormalities. EEG abnormalities increased with advancing age independently of IQ development and showed no relation to either the age at the onset nor the quality of dietary treatment.

Changes in the EEG background activity of children with acute lymphoblastic leukemia during cytotoxic therapy.

Thirteen children with acute lymphoblastic leukemia (ALL) were investigated before and during cytotoxic therapy. EEG findings were correlated with the clinical course and the therapy protocol and compared with normal data obtained from 295 healthy children. Frequency analysis of the background activity of the EEG revealed an initial slowing of the background activity prior to therapy and further slowing each time a combination of vincristine (VCR), daunorubicin (DAU) or adriblastine (ADR), prednisone (PRED), and L-asparaginase (L-ASP) was administered. The slowing of the background activity correlated only with the administration of these drugs. DAU, ADR, and PRED are not known to influence the EEG; therefore, VCR and L-ASP remain the primary candidates responsible for the central nervous system alteration.

Spectral analysis of the EEG in children during the introduction of antiepileptic therapy with valproic acid.

The EEGs of 16 newly diagnosed children with primary generalized epilepsy were examined before and during up to 3 years of antiepileptic therapy with valproic acid. Spectral analysis was performed and parameters of the relative power within the conventional frequency bands were compared with norm data. Before treatment no significant differences of the background activity between epileptic children and healthy controls were found. While treatment was able to reduce seizures and spike-wave activity, EEG parameters did not change systematically. There was no relation between valproate serum levels and parameters of the background activity.

EEG development of healthy boys and girls. Results of a longitudinal study.

This longitudinal study has extended an earlier cross-sectional one in order to investigate the development of background activity and the topographical distribution of different EEG parameters during childhood and adolescence. Ninety-six healthy children (47 boys and 49 girls) were followed for up to 7 years with serial EEGs. These were analysed by spectral analysis. Power spectra were calculated for conventional frequency bands. Three topics were followed: (i) differentiation between inter-individual and age-related changes, (ii) evaluation of sex differences and (iii) evaluation of developmental velocity of different EEG parameters. Between 4 and 17 years the content of theta waves decreases and the content of alpha waves increases. In girls more than in boys, slow alpha waves (7.5-9.5 c/sec) in occipital leads first increase, as theta decreases. Later they decrease themselves while fast alpha waves (9.5-12.5 c/sec) increase. The velocity of occipital changes is almost twice that centrally, and is greater in early childhood than after 10 years of age. Girls under 6 years of age show significantly more theta and less alpha waves compared with boys. However, the developmental velocity (change per year) is higher in girls than in boys and continues for a longer time; thus girls catch up with age-related changes of the boys by a later developmental spurt. Individual characteristics of the subjects determine the EEG twice as much as the age factor; this explains the wide range of results in previous studies. No trend was found to suggest earlier maturation in one hemisphere while in 5% of the subjects the amount of activity for one parameter in one hemisphere exceeds 1.5 times the amount of activity in the other. The individual characteristics of the EEG spectra show a remarkable stability over the years.

Spectral analysis of the EEG: comparison of various spectral parameters.

One of the main problems in spectral analysis of the EEG consists of finding relevant parameters which are capable of summarizing all information included in the power spectrum. The mathematical properties and the clinical applicability of 4 sets of parameters were compared: (1) percentage of power within the conventional frequency ranges, (2) mobility and complexity (Hjorth), (3) the slope parameter (Dumermuth), (4) the coefficients of the autoregressive model. They were applied to the EEG changes in a child with brain stem tumour during cerebral radiotherapy. The statistical analysis suggests: (I) there are only minor differences in describing the EEG course between the conventional frequency ranges, mobility and the slope parameter, (II) the complexity is less satisfactory, (III) the first autoregressive coefficient of the AR model yields the best results.

Changes in the background activity of the electroencephalogram according to age.

Spectral analysis of the background activity of the EEG was performed in 295 healthy children, 4--11 years old, using the relative powers of theta (3.5--7.0 c/sec), slow alpha (7.5--9.0 c/sec) and fast alpha (9.5--12.5 c/sec) bands. Non-parametric regression functions of spectral parameters were estimated using Rosenblatt's method. The correlation with age is best represented by the logarithmically transformed value of fast alpha activity in the occipital leads (r = 0.5783 for O2 and 0.5657 for O1). Differences between corresponding points of the two hemispheres are small. The fast alpha activity is slightly more prominent in central leads up to 8 years of age but becomes dominant occipitally after that age. In the maturation of the EEG there are significant differences between boys and girls: the mean percentage of slower activity is higher, and of faster activity is lower, in girls than boys. Thus the EEG maturation in girls up to 11 years seems to be retarded compared with boys.

Extracellular calcium and potassium changes in hippocampal slices.

Ca2+ and K+ ion sensitive microelectrodes were used to measure changes in ionic activities in the CA1 region of hippocampal slices during orthodromic (stratum radiatum) stimulation. Baseline levels of [K+]o and [Ca2+]o were those of the bathing medium which contained 5 mM K+ and 2.0 mM Ca2+. During stimulation [K+]o rose to maximal levels of 12 mM while [Ca2+]o decreased to as low as 1.4 mM. Systematic alterations in extracellular field potentials in stratum pyramidale accompanied the ionic shifts. Following stimulation K+ undershoots occurred. An active K+ uptake mechanism was demonstrated using iontophoretic K+ pulses. [K+]o and [Ca2+]o changes occurred in parallel and in a laminar distribution with maximal changes recorded in stratum pyramidale. Maximal [K+]o changes occurred from baselines of 5 mM and declined progressively at higher baseline levels. During epileptiform activity produced by exposure of slices to penicillin, larger ionic shifts with a more rapid onset occurred. The alterations in [K+]o and [Ca2+]o in the hippocampal slice are similar in some respects to those obtained by stimulation in vivo, making this preparation a potentially useful one for determination of mechanisms and effects of alterations in the ionic microenvironment.

Calcium-sodium antagonism on the frog's heart: a voltage-clamp study.

1. In double sucrose-gap voltage-clamped frog atrial fibres the influence of [Ca]o and [Na]o on membrane current and contraction was investigated. 2. The slow (secondary) inward current varied with [Ca]o but was almost insensitive to changes in [Na]o. In contrast, the phasic (transient) contraction initiated by the slow inward current was affected by both [Ca]o and [Na]o. 3. With moderate changes of [Ca]o and [Na]o from normal, the strength of phasic contraction at a given depolarization followed the [Ca]o/[Na]2o ratio approximately. This was best seen at membrane potentials near zero level. 4. Under the same conditions, tonic (sustained) contractions associated with prolonged depolarizations were strictly correlated to the [Ca]o/[Na]2o ratio at any potential. No interrelation between tonic tension and steady-state current was found. 5. With extensive changes in [Ca]o and [Na]o, the sensitivity of both phasic and tonic tension to the [Ca]o/[Na]2o ratio declined, the negative effect of [Na]o becoming smaller than was expected from this ratio. 6. In Na-free choline-Ringer, a strong contracture developed followed by a spontaneous relaxation. Starting from the relaxed state, application of depolarizing clamps gave rise to phasic contractions with a very slow relaxation while tonic contractions were apparently lacking. 7. The results are interpreted in terms of an energy-dependent carrier mechanism exchanging one Ca for two Na ions across the cell membrane. The model implies a strong asymmetry in the rate constants governing the chemical reactions on both sides of the membrane. The system is thought to operate close to equilibrium at any potential, thereby determining the steady level of myoplasmic Ca. The equilibrium itself is considered to shift upon depolarization. Assuming that [Na]i is constant, the steady level of [Ca]i is expected to be proportional to the [Ca]o/[Na]2o ratio, the scale factor being a function of membrane potential. 8. The carrier model suggests the occurrence of a depolarization-induced inward transfer of Ca which might be involved in the generation of tonic contractions. 9. The apparent lack of tonic contractions in the absence of external Na ions may be explained by a suppression of carrier-mediated Ca influx normally occurring upon depolarization. 10. The antagonistic effects of [Ca]o and [Na]o on phasic contraction are understood as being due to alterations of the Ca pumping system rather than changes in slow inward current.

Effects of prenylamine on cardiac membrane currents and contractility.

The influence of prenylamine on the electrical and mechanical activity of frog atrial muscle fibers has been studied under voltage clamp conditions. At a concentration of 10-4 M, prenylamine blocks the action potential without much affecting the resting potential. The drug depresses the peak transient sodium conductance with a dissociation constant of 1.7 times 10-5 M and on a one-to-one stoichiometric basis. The curve relating peak sodium conductance to membrane potential is slightly shifted in the direction of hyperpolarization. The time to peak sodium current and the rate of sodium inactivation are not significantly altered. With 2 times 10-5 M prenylamine, the steady-state sodium inactivation curve is shifted by 5 mV to more negative membrane potentials but the decreased availability of the sodium system at the resting level is not sufficient to account for the reduction of sodium current. Recovery from sodium inactivation upon repolarization is distinctly slowed. The slow (secondary) inward current carried by calcium and/or sodium and the steady-state outward current are also depressed by prenylamine. The phasic (twitch-like) contraction related to the slow inward current is slightly decreased. The tonic (sustained) contraction associated with long-lasting depolarizations is increased and the time course of relaxation is retarded by prenylamine.