Long-term follow-up study of "epileptic type" moyamoya disease in children

Twenty-three patients with epileptic type moyamoya disease are reviewed among 200 moyamoya disease patients. Ten boys and 13 girls aged 5 months to 12 years were followed over 6 months to 17.3 years. Six had generalized seizure and 17 had focal seizure. Operations were performed within 1 year in eight patients, within 1-3 years in five, and more than 3 years after onset in 10. Nineteen patients improved and suffered no seizure without receiving antiepileptic drugs, but four patients developed true epilepsy and three of these suffered cerebral infarction. Multivariate analyses showed that toddlers aged less than 1 year and mild or severe abnormal computed tomographic (CT) findings correlated with a bad outcome. This study showed that epileptic type moyamoya disease has the same clinical features as transient ischemic attack or infarction type. Age under 1 year and CT abnormalities indicate a poor prognosis and necessity for early reconstructive surgery.     

Salivary immunoglobulin concentrations in patients with epilepsy treated with carbamazepine

Various anti-epileptic drugs may affect the immune system. An IgA-depressing effect of carbamazepine has been proposed, but only serum concentrations have been studied. IgA constitutes a small fraction of the serum immunoglobulins, while it is the predominating one in external secretions. In the present study the concentrations of IgA, IgG and IgM in unstimulated saliva were determined by single radial immunodiffusion in 34 patients with partial epilepsy, and being treated with carbamazepine alone. Median salivary IgA concentration in the patients was 208 x 10(-3) g/l, compared to 150 x 10(3) g/l in 41 healthy controls. Salivary IgG and IgM concentrations were also somewhat higher in the patients than in the controls, while the albumin concentrations were similar in the two groups. However, the differences in the immunoglobulin concentrations between patients and controls were not significant at a 5% level. There was no significant correlation between the concentrations of IgA in saliva and serum.     

Serum uric acid concentration and anticonvulsant therapy in childhood

In antiepileptic treated adults a decrease of serum uric acid concentration was reported. In contrast to these findings we did not find a general decrease of uric acid concentration in 233 studied epileptic children and juveniles treated with antiepileptic drugs. But we found a significant decrease of uric acid concentration in epileptic children and juveniles treated with carbamazepine in monotherapy as well as in combined treatment. Rather increased uric acid serum concentration were found in primidone and valproate monotherapy. In the studied age groups only carbamazepine seems to be able to diminish uric acid concentration. The underlying mechanisms are unknown.     

Serum and intestinal fluid immunoglobulins and jejunal IgA secretion in Crohn's disease

Immunoglobulins in serum and proximal intestinal fluids and secretion of IgA by cultured jejunal mucosa were measured in 12 healthy subjects and 36 patients with Crohn's disease. Concentrations of IgA, IgG, IgM, and IgE in serum and intestinal fluids were similar in the two groups, except for increased serum IgA concentrations in the patients. Elevation of IgA and chronicity of disease were correlated, which suggests that the IgA alteration was a response to duration of disease rather than a primary pathogenetic factor. IgA secretion by cultured jejunum was similar in control and patient groups. Thus, no evidence was found that abnormalities of secretory immunoglobulins are pathogenetically involved in Crohn's disease.     

Changes in serum immunoglobulin levels during phenytoin treatment of epilepsy

Immunoglubulin concentrations were determined by radial immunodiffusion in sera from 15 epileptic patients before and during phenytoin therapy. Three reaction patterns were recorded: Two patients developed IgA deficiency (less than 0.05 mg/ml) during the first 3-4 months of treatment. Both patients also had a decrease in serum IgG and IgM, but no significant fall or increase in serum IgE. The IgA deficiency state was apparently reversible, since normalization of serum levels occurred after withdrawal of phenytoin. Five patients developed a 35-80 per cent reduction in serum IgA. In these patients, the decline in serum levels of IgG and IgM was inconsistent. Eight patients showed no significant fluctuations in serum immunoglobulins during phenytoin treatment. When a fall in serum IgA occurred, it did not correspond to a fall in serum or in red cell folate. Mean serum IgG was lower (9.37 mg/ml) in epileptic patients who had taken phenytoin for less than 1 year and had a low IgA, than in patients who had taken phenytoin for 10 years or more (11.50 mg/ml).     

Color vision tests for early detection of antiepileptic drug toxicity

A previous suggestion that antiepileptic drugs may induce color vision deficiencies prompted us to examine whether color vision deficiencies may occur at lower drug serum concentrations than those associated with symptoms of neurotoxicity. Eighty patients presenting with epilepsy received monotherapies of valproic acid, phenytoin, or carbamazepine; 18 patients did not receive antiepileptic drug therapy. Color vision was tested by the Farnsworth-Munsell 100-hue test, spectral sensitivity, and the newly developed tritan screening plates. Patients treated with phenytoin or carbamazepine developed blue-yellow color vision deficiencies. In contrast, patients exposed to valproic acid or receiving no drug treatment showed normal color vision. There was a significant correlation (p < 0.0001) between signs of neurotoxicity induced by phenytoin or carbamazepine and blue-yellow color vision deficiencies. In contrast, we found no correlation between these signs of neurotoxicity and the drug serum concentrations (p = 0.0637). Color vision testing in epileptic patients treated with phenytoin or carbamazepine appears to be a sensitive method for early detection and monitoring of clinical neurotoxicity.     

When and how should the long-term anti-epileptic treatment be stopped

Although for some decades it has been customary to stop long-term treatment of epilepsy in patients who have been free of crises for several years, there is still no general agreement as to when, how and in which cases such treatment should be stopped. Several factors have to be taken into account when making such a decision: the known toxicity of anti-epileptic drugs; the fact that 10-20% of the patients on such treatment have recurrences of their epileptic crises and that around 25% of the children and 40% of the adults relapse when long-term treatment is stopped. On the other hand, factors which reduce the risk of relapse have recently been identified. When the psychological benefit of no longer having to take anti-epileptic drugs together with their high cost are also considered, it would seem advisable to stop treatment when the patient has had no epileptic crises for several years. Since there is no significant difference in the frequency of relapses when anti-epileptic drugs are suspended 2-5 years after the last crises, and these crises are more frequent when paroxystic activity is seen on the EEG before stopping the drugs, we recommend that treatment be stopped after 2 years free of crises in idiopathic epilepsy, after 3 years with no sign of abnormality in the EEG in patients with partial cryptogenic epilepsy and after at least 4 years without crises and 2 years of normal EEG in patients with partial symptomatic or generalized cryptogenic or symptomatic epilepsy. The criteria for suspending drug treatment should take account of the pharmacokinetic features and permit EEG control. Therefore we recommend that 40% of the total dose be stopped during the first 6 months at a rate of 20% every three months and then a further 20% every two months until medication has been stopped completely.     

Embryofetopathy due to valproate: a pathology only little known. Apropos of 4 cases

BACKGROUND: Sodium valproate administration during pregnancy may be teratogenic; it is associated with an increased risk of neural tube defect, tetralogy of Fallot, oral clefting and other facial abnormalities. Knowledge of these harmful effects is still poor. CASE REPORTS: Four children, including three siblings, presented with characteristic facial abnormalities (four cases), oral clefting (one case), mental retardation (2/2 cases), and bone anomalies of forearm and hands (one case). The diagnosis of fetal valproate syndrome was only made at the age of 3 1/2 years in the eldest of the three siblings all born from an epileptic mother receiving valproate since the age of 13 years. Prevention advice for further pregnancies was not followed. CONCLUSION: All epileptic mothers should be aware of the risk of antiepileptic drugs during pregnancy, specially those given sodium valproate, a potentially teratogenic drug.     

Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs

1 The serum concentration profile of paracetamol has been determined after administration of single 1000 mg intravenous and oral doses in six normal subjects and six epileptic patients on chronic antiepileptic drug therapy. The urinary excretion of free and conjugated paracetamol has also been determined. 2 Following intravenous administration, serum paracetamol concentration declined with first-order kinetics. Both elimination rate and total body clearance were higher in the epileptic patients, although in neither case was the difference statistically significant. 3 The oral bioavailability (mean +/- s.e. mean) was significantly lower in the epileptic patients than in the normal subjects (0.77 +/- 0.03 and 0.89 +/- 0.02 respectively, P less than 0.01), whereas the urinary excretion total (free+conjugated) paracetamol was almost identical in the two groups. 4 It is suggested that the lower bioavailability of paracetamol in the epileptic patients results from enhancement of first-pass metabolism, secondary to enzyme induction.     

Influence of a potential anti-asthmatic drug, CR 2039, upon the anticonvulsive activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

CR 2039 [[4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl]phenylbenza m ide], in doses of 10, 50, and 100 mg/kg i.p., significantly elevated the threshold for electroconvulsions, increasing the CS50 (current strength 50% in mA) values from 6.3 to 7.2, 7.5, and 7.6 mA, respectively. When combined with carbamazepine, diphenylhydantoin, or valproate, CR 2039 (5 and 10 mg/kg) potentiated the anticonvulsive action of these antiepileptics against maximal electroshock-induced convulsions which was reflected by significant decreases in the respective ED50s (in mg/kg). The protective efficacy of phenobarbital was not affected by the phenylbenzamide derivative. The potentiation of the anticonvulsive activity of three antiepileptics was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (10 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied which speaks against a pharmacokinetic mechanism in the observed results. It is concluded that CR 2039 may prove a safer anti-asthmatic drug for the use in epileptic patients than aminophylline which, either acutely or chronically, considerably impaired the anticonvulsive activity of conventional antiepileptics.     

How often and what type of control tests should be done during long- term anti-epileptic treatment?

During long-term epileptic treatment, it is essential to monitor the efficacy of the drugs used. Any adverse effects of this treatment must be detected early or preferably avoided. However, the type of control and the frequency with which this should be carried out are controversial. All anti-epileptic drugs are potentially liable to provoke adverse reactions of different types and degrees. Determinations of the blood-levels of anti-epileptic drugs are useful to attain optimus drug levels, and to identify any relationship there might be between these drugs and possible adverse effects. However, this usefulness varies, depending on the particular anti-epileptic drug concerned. Therefore measurement as a routine is not justified, but should be undertaken to obtain the answer to specific questions. Laboratory analysis of blood to determine liver function, blood cell counts, coagulation, etc. is necessary in some cases. This may imply problems of interpretation and of cost. Is most cases it is of little help in the early detection or prevention of the most serious adverse reactions, which cause the greatest mortality. Therefore although such measures are necessary, attention should be paid to clinical methods for the early detection of symptoms and signs which may indicate the presence of adverse effects. Similarly, EEG should not be done as a routine for the assessment of the effect of treatment, but should be used when indicated for the follow-up of specific epileptic syndromes. An EEG may be useful for prognosis before suspending long-term epileptic treatment.     

Micellar electrokinetic capillary chromatography for therapeutic drug monitoring of zonisamide

The simultaneous determination of zonisamide, a new type of antiepileptic drug, and the typical antiepileptic drugs phenobarbital, phenytoin and carbamazepine in human serum was developed using micellar electrokinetic capillary chromatography (MECC) with a diode array detector. A high correlation was revealed between the zonisamide levels in human serum obtained by MECC and those obtained by high-performance liquid chromatography (r=0.981). The serum levels of phenobarbital, phenytoin and carbamazepine determined by MECC were almost equal to those obtained by fluorescence polarization immunoassay. The reproducibility of separation and quantification with MECC analysis was appropriate for the intra- and inter-day assay coefficients. Therefore, the MECC method established here could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs in patients, especially those treated with a combination of zonisamide and other antiepileptic drugs.     

Isoniazid as an inhibitor of primidone metabolism

Isoniazid inhibited the metabolism of primidone in a patient with focal seizures. The steady-state serum level of primidone rose when the patient received both drugs simultaneoulsy. The serum levels of the primidone metabolites, phenobarbital and phenylethylmalonamide, fell and the rate of metabolism of primidone decreased. The results are similar to those observed when isoniazid is adminstered with diphenylhydantoin.     

Memory and epilepsy

INTRODUCTION: The neuropsychological literature has shown the presence of memory deficits in patients with epilepsy. These alterations in memory are due to several factors, such as the aetiology of the epilepsy, age at onset of the seizures, the duration of the disorder, and the frequency and type of the epileptic seizures. DEVELOPMENT: These memory defects reflect the structural and functional damage caused by the repeated epileptic seizures and/or the anti-epileptic drugs. Apart from this, neuro-surgical treatment of temporal lobe epilepsy may also lead to memory defects. These will depend on the site and side of the epileptic focus, the level of memory prior to surgery, the age of onset of the epileptic seizures, the chronological age at the time of operation and the reduction in the number of seizures after surgery. In spite of the evidence that memory is affected in patients with epilepsy, this does not mean that all people with epilepsy have these changes. CONCLUSIONS: Neuropsychological examination is of fundamental clinical importance since it allows the evaluation of cognitive function in each patient, and thus permits optimization of both the pharmacological treatment and intellectual and physical performance.     

Role of vigabatrin and lamotrigine in treatment of childhood epileptic syndromes

PURPOSE: Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes. METHODS: We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies. RESULTS: VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies. CONCLUSIONS: VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add-on to other AED treatment.     

Bilateral horizontal gaze palsy with pontine cavernous hemangioma: a case report

Epilepsy is a common condition. In most cases, treatment with medications is satisfactory. When antiepileptic drugs fail to control the seizures, further evaluation may be warranted. EEG-video monitoring can allow a definitive diagnosis of epileptic seizures to be made by differentiating epileptic events from paroxysmal symptoms that can be mistaken for seizures (i.e., pseudoseizures). In addition, it usually allows one to accurately diagnose the seizure type, facilitating selection of the best possible treatment. Occasionally, surgery may be a therapeutic option in patients with intractable seizures.     

Epilepsy and the heart

The relations between epilepsy and heart are complex and expressed in two opposite sides. (1) Cardiac arrhythmias may provoke epileptic seizures but these seizures are, in this case, syncopal attacks. Nevertheless, in the past, these clinical features have been individualized as "cardiac epilepsy" or epilepsy in cardiacs. However, true epileptic seizures could be observed in the course of a syncopal attack and a syncope may complicate the issue of an epileptic seizure. (2) On the other hand, epileptic seizures may provoke severe cardiac arrhythmias. The incidence rate of sudden death in patients with epilepsy is estimated to be 1/1000 patients. The exact neural mechanisms in cardiac arrhythmias seizures could explain only some of the sudden unexpected deaths observed in epileptic patients. The role of antiepileptic drugs on cardiac conduction as well as the effects of seizures or status epilepticus on the myocardium are other enigmatic aspects of the relations between epilepsy and heart.     

Evaluation of the effect of long term valproic acid treatment on plasma levels of carnitine, ammonia and amino acids related to the urea cycle in pediatric epileptic patients

INTRODUCTION: Valproic acid (VPA) is an antiepileptic drug widely used in paediatrics. In spite of being a safe and effective anticonvulsant, VPA has been involved in the onset of changes in the metabolism of ammonia and carnitine, although few prospective studies have been made of this. OBJECTIVES: To evaluate the effect of long-term VPA administration, particularly on the metabolism of carnitine, ammonia and plasma amino-acids and the possible clinical repercussions of this in a group of epileptic patients studied prospectively and retrospectively. MATERIAL AND METHODS: A study was made of 102 epileptic children on long term anticonvulsant treatment mainly with VPA. These patients were divided into two groups: group I (n = 25) were studied prospectively (basal sample, after one, six and twelve months of treatment) and group II (n = 77) or long term treatment group (a single sample extraction). In each epileptic patient and in 56 children from a control group (group III) studies were made of free plasma carnitine, ammonia and amino-acids related to the urea cycle and the plasma levels of each anticonvulsant drug. RESULTS: It was observed that in group I there was a fall in plasma carnitine concentrations with time and a progressive rise which was statistically significant (p = 0.001) in plasma levels, mainly of ammonia, glutamine, glycine and ornithine, from the basal levels to those after a year of treatment in practically 100% of the children studied. In group II children on antiepileptic drugs, mainly VPA, were seen to have lower plasma carnitine levels than those in the control group and higher serum ammonia, glutamine and glycine levels than the healthy population not treated with anticonvulsants. These differences were statistically significant (p = 0.001). No relationship was found between the parameters studied and the plasma levels of the drug, type of epilepsy or presence of side effects. CONCLUSIONS: These changes show the negative effects of VPA on the metabolism of carnitine and ammonia. It would therefore seem advisable to monitor these parameters in epileptic children on long term antiepileptic treatment.     

Lennox-Gastaut syndrome--clinical course and therapy

Clinical course and results of therapy were analysed in the group of 92 children, aged between 3 and 9 years, with diagnosed Lennox-Gastaut syndrome. The obtained results of an analysis have shown that Lennox-Gastaut syndrome origin is not clear--causative factor can not be established in 1/3 of patients whereas in 1/2 of them abnormal course of pregnancy and perinatal period is noted. Together with seizures of various origin, other focal neurological symptoms, mental retardation and abnormalities in CT scans of the brain are frequently seen in patients with Lennox-Gastaut syndrome. Clinical course, prognosis and results of therapy are largely dependent on the degree of mental development before the onset of epileptic seizures, course of pregnancy and perinatal period, and the time of therapy. Children with Lennox-Gastaut syndrome require relative polytherapy in which valproic acid derivatives are predominating together with benzodiazepines, and temporary corticosteroids. An improvement was achieved in about 30% of the treated children. Prognosis in the remaining 70% of children is rather poor. Irregular administration of drugs, frequent changes of anti-epileptic agents, too low doses and abnormal environmental effects (abnormal parental attitudes) affect the results of therapy. An emphasis is on the poor prognosis in Lennox-Gastaut syndrome proceeded with West syndrome.     

A severe case of Moebius syndrome with calcification on the fourth ventricular floor

Disturbance of metabolism of trace elements and antioxidants are investigated in epileptic patients with long-term therapy of anticonvulsants. One hundred and fifteen subjects including healthy controls, untreated epileptic patients, and phenytoin (PHT)- or carbamazepine (CBZ)-treated epileptic patients were recruited in this study. Serum malondialdehyde was measured as an index of extracellular lipid peroxidation. The levels of serum copper (S-Cu), serum zinc, copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione in the serum were monitored simultaneously. The results showed that malondialdehyde, S-Cu, and CuZn-SOD levels in the serum all were significantly increased, but the glutathione level was significantly decreased, in all the epileptic patients with PHT monotherapy compared with those of the controls. However, no significant differences of these parameters in the epileptic patients with CBZ monotherapy were found except for a mild elevation of the activity of serum CuZn-SOD. We conclude that compared with PHT monotherapy, the CBZ monotherapy induced less disturbance in trace element metabolism, antioxidants, and lipid peroxidation in the serum of epileptic patients.