Dieter Janz

Neuropathological Findings in Primary Generalized Epilepsy: A Study of Eight Cases

Summary: On neuropathological investigation of eight cases with primary generalized epilepsy, none showed elective parenchymal necrosis, which is regarded (qualitatively and topologically) as characteristic of epilepsy in classical neuropathology. In seven of the eight cases, however, marked microdysgenesis with varying regional distribution was found. These maturation disturbances are to be interpreted as pathological and refute the currently held view that there is no evidence of pathological brain damage in primary generalized epilepsy.

Epilepsy with impulsive petit mal (Juvenile Myoclonic Epilepsy)

ABSTRACT – Juvenile myoclonic epilepsy (JME) is a special syndrome within the primary generalized epilepsies which is characterized clinically by irregular jerks of shoulders and arms (so‐called impulsive petit mal) after awakening and electroencephalographically by bilateral‐synchronous 4–6/s spike‐wave complexes, often in the form of multispike‐waves. The age of onset for this syndrome which occurs in 4–6% of all epilepsies is predominantly between 12 and 18 years. It mostly starts with isolated jerks which as a rule are soon followed by generalized tonic‐clonic seizures (TCS). Jerks and TCS are provoked by sleep deprivation and predominantly occur after awakening (awakening epilepsy). Sleep deprivation and photostimulation are also very efficient in provoking specific EEG patterns. Exogenous factors have no etiological significance. Genetic studies suggest a polygenetic mode of inheritance and a lower threshold of manifestation in women. JME can be controlled very well by valproate and/or primidone. A complete cure, nevertheless, does not seem to be possible. Within the group of primary generalized epilepsies beginning in adolescence JME is closely related nosologically to the syndrome of juvenile absences and the syndrome of pure grand mal on awakening.

The Significance of Microdysgenesia in Primary Generalized Epilepsy: An Answer to the Considerations of Lyon and Gastaut

According to the proposal of Gastaut (1969) for an international classification of epilepsies, primary generalized epilepsies are characterized by a specific EEG pattern as well as by the fact that there is no morphological brain damage to be found. As a result of our study of eight cases of primary generalized epilepsy (Meencke and Janz, 1984), to which Lyon and Gastaut refer (1983, we came to the conclusion that brain damage, considered until now to be a consequence of seizures, was not seen despite frequent grand ma1 seizures. However, the brains were not without morphologically significant findings. In almost all cases there were findings in the brain which had to be characterized as “microdysgenesia” and which we interpret as being pathological and a manifestation of minimal developmental disturbances. It is because this would call into question the current definition of primary generalized epilepsy that Lyon and Gastaut ask for the pathological significance of these minor histological features, for their confirmation by controls, and for their quantification by morphometric analysis. Their questions give an opportunity for us to clarify some misunderstandings and to show the future direction of the questions that are required to arrive at new concepts.

The Teratogenic Risk of Antiepileptic Drugs

Nearly all studies on the topic of teratogenic risks of antiepileptic drugs have concluded that congenital anomalies occur more frequently among children from mothers with epilepsy who took antiepileptic drugs during pregnancy than among children from motkrsfree of epilepsy or children from epileptic mothers who did not take any antiepileptic drugs during pregnancy. Among the malformations, cleft lip (with or without cleft palate) and congenital heart lesions are particularly noted. It has been suggested that these malformations are induced by antiepileptic drugs, since teratogenic effects have been induced in experiments on animalsunder rather artificial conditions, however, as the antiepileptic drugs pass through the placenta. Diphenylhydantoin (DPH) has been suspected to be especially teratogenic, since cleft lip and cleft palate have been induced-in certain strains of mice and under extreme conditions, however-by DPH ingestion. This suspicion is a grave one. A lot is at stake. Should these drugs, which have helped uncounted numbers of people, be held responsible for these damaging effects? The problem concerns approximately 0.3 to 0.5% of all pregnancies. Of all pregnancies studied in Saint Thomas Hospital, London, 0.28% were those of epileptic mothers (South, 1972). In Norway, the number was 0.28% (Bjerkedal and Bahna, 1973); in Cardiff, 0.42% were recorded (Speidel and Meadow, 1972); and 0.54% were affected in Groningen (Elshove and Van Eck, 1971). It is, therefore, urgent to know if there is an increased risk for malformations, what its measure is, and what

Antiepileptic Drugs and Pregnancy: Altered Utilization Patterns and Teratogenesis

Although we have long known that the course of epilepsy can change for the better or worse during pregnancy, the reasons for such changes are not known. Pregnancy does not in itself cause either epileptic seizures or the occurrence of a status epilepticus. Studies have shown that in about one-quarter of women who have had seizures prior to becoming pregnant, seizure frequency increases during pregnancy (Fig. 1). In another quarter of this population seizure frequency decreases during pregnancy, and in about half of the group there is no change (1). More recent prospective studies show somewhat greater variability-ranging from 8 to 46%-although the average is the same for increase in seizure frequency (2-5). A variety of physiological mechanisms and psychological factors have been put forth as possible causes for this increase (Table 1). Experimental findings and clinical evidence have yet to establish a correlation between hormonal or metabolic changes during pregnancy and the number of seizures. There have been no controlled studies on the influence of pregnancy-related psychological problems in women with epilepsy. It has been suggested that ambivalence toward the child or husband and tension and anxiety can lead to loss of sleep or hyperventilation, which can in turn precipitate seizures. Also, psychological problems may result in irregular medication during pregnancy, and the resultant fall in the plasma concentration of antiepileptic drugs may contribute to an increase in seizure frequency. Recent observations have shown that the plasma concentration of antiepileptic drugs tends to fall during pregnancy and to increase during the puerperium (6). No large-scale investigations of ethosuximide and valproate disposition during pregnancy have been made. A decrease in the plasma concentration of the frequently prescribed drugs phenytoin, phenobarbital, and carbamazepine has often been observed (Figs. 2 and 3). However, the extent and the time course of the decrease vary considerably among drugs and individuals, and during different pregnancies in the same individual ( 7 3 ) . Mean values of the plasma concen-

Generalized Tonic-Clonic Seizures in Patients with Complex-Partial Seizures: Natural History and Prognostic Relevance

Summary: Clinical course and long‐term seizure prognosis were studied in 155 patients with complex‐partial seizures during a follow‐up of 10.1 ± 1 (SD) years. In 79% of the patients generalized tonic‐clonic seizures were recorded, mostly within the first 3 years of epilepsy but occurring as late as 20 years after the onset of epilepsy. Seizure control was defined as complete absence of all seizures, including auras, for a minimum of 2 years. Seizure control occurred in 20 of 32 patients (63%) with complex‐partial seizures only and in 76 of 123 patients (62%) with complex‐partial seizures and generalized tonic‐clonic seizures. The onset of the epilepsy with generalized tonic‐clonic seizures or complex‐partial seizures did not influence the therapeutic outcome despite differences in their natural history. A family history of epilepsy and other generalized seizures (e.g., absence) were more frequent in patients with generalized tonic‐clonic seizures at the onset of epilepsy. Seizure control was significantly lower (44%) in patients with a history of a maximum frequency of one or more generalized tonic‐clonic seizures per month when compared to patients (79%) with a total of less than six generalized tonic‐clonic seizures (p < 0.05). The frequency of generalized tonic‐clonic seizures is of predictive value for the seizure prognosis of patients with complex‐partial seizures.

Possible Association of Juvenile Myoclonic Epilepsy with HLA-DRw6

Summary: Juvenile myoclonic epilepsy (JME) is a clearly defined subform of idiopathic generalized epilepsy with a high aggregation of epilepsy in family members. With the HLA‐system used as a genetic marker, a linkage between JME and the HLA region was demonstrated. Linkage with the HLA region suggests that JME may be associated with an HLA‐antigen. An association could indicate that the gene lies in the HLA region and is in linkage disequilibrium with one of the HLA‐antigens. Eightyeight unrelated patients with JME were typed for the HLA‐A and HLA‐B locus, 77 were typed for the HLA‐C locus, and 76 were typed for the DR locus. The antigen frequency was compared with those of healthy blood donors. The highest difference was noted in the frequency of DRw6 (39.5% in patients vs. 22.1% in controls). This weak association is open to question because DRw6 is known to split into DRwl3 and DRw14.

Neurological Morbidity of Severe Epilepsy

Summary: : The “severity” of a disease is a relative expression and its definition will vary depending on the perspective of the observer. The patients subjective perception of the disease, the way it is regarded socially by the community, and the doctors objective assessment rarely coincide. In fact, they are frequently diametrically opposed. As far as the patients personal perception of epilepsy is concerned, there has apparently been no satisfactory attempt thus far at a systematic grading of the subjective handicap, despite the growth of interest in psychological matters and the self‐help movement. Similarly, social ability or disability cannot be adequately assessed on the basis of medical criteria such as frequency and type of seizures. We present a grading system which will serve as an example of an appropriate method of assessing social abilities, and which will permit the patients occupational potential to be estimated in relation to the risk of accidents resulting from seizures. From the medical point of view, the impairment of a patients abilities due to epilepsy is a function of the patients responsiveness to treatment. We present a critical review of the factors which have an effect on the therapeutic prognosis: the causes of epilepsy, underlying structural lesions, the incidence of convulsive status epilepticus, various types of attacks, and the different epileptic syndromes. Taking two examples–epilepsy presenting in the form of absence and epilepsy with complex focal seizures–we show that ultimately the “severity of epilepsy” can only be defined from the medical standpoint on the basis of several factors whose value is of a predictive nature.

Epilepsy, Viewed Metaphysically: An Interpretation of the Biblical Story of the Epileptic Boy and of Raphael's Transfiguration

Summary: Raphaels last painting reveals, in the upper half of the picture, Christs transfiguration on Mount Tabor and, in the lower half, the young boys epileptic seizure at the foot of the mountain in the presence of the other disciples. Raphael depicts both events, which are told in succession in the Gospels, as if they took place at the same time. By synchronizing both scenes Raphael demonstrated a significant correspondence between Christ and the epileptic boy, which reveals the epileptic seizure as a symbolic representation of a transcendent event. This metaphysical aspect of epilepsy depicted by Raphael can also be found in the corresponding biblical passages. In the Gospels, the metamorphosis caused by the epileptic seizure is used as a simile for Christs transfiguration through suffering, death, and resurrection.

Comparison of spectrophotometric and gas-liquid chromatographic measurements of serum diphenylhydantoin concentrations in epileptic out-patients.

SummaryIn 127 epileptic out-patients treated only with diphenylhydantoin its mean serum concentration was measured by Kupferbergs gas chromatographic and Svensmarks spectrophotometric method [10, 15]. The spectrophotometric method gave with 17.4±11.3 μg/ml (±S.D.) significantly higher mean serum concentrations (P<0.0005) than the gas chromatographic method with 11.7±9.2 μg/ml (±S.D.). The difference could be due to a higher specificity of the gas chromatographic method or a lower yield of its extraction procedure. Accuracy was higher with the gas-liquid chromatography. A correlation coefficient ofrglc/sv=0.7552 between the results of both methods was determined.Women had a significantly lower mean serum concentration of diphenylhydantoin (P<0.05) in the dose range of 4.0–5.9 mg DPH/kg although a higher dose per kilogram body weight had been administered. This could possibly be due to sex hormone influence.ZusammenfassungBei 127 ambulanten Epilepsie-Patienten mit reiner Diphenylhydantoin-Medikation wurde die Serumkonzentration sowohl gaschromatographisch (nach Kupferberg) als such spektrophotometrisch (nach Svensmark) bestimmt [10, 15]. Die spektrophotometrische Methode führte mit 17,4±11,3 μg/ml (±S.D.) zu signifikant (P<0,0005) höheren Werten als die gaschromatographische Methode mit 11,7±9,2 μg/ml (±S.D.). Die Differenz kann durch eine höhere Spezifität oder durch eine niedrigere Extraktions-Ausbeute bei der gaschromatographischen Methode bedingt sein. Die gaschromatographische Methode lieferte genauere Ergebnisse als die spektrophotometrische Methode. Aus den Ergebnissen beider Methoden wurde ein Korrelationskoeffizient vonrglc/sv=0,7552 errechnet.Obwohl Frauen eine höhere Dosis pro Kilogramm verordnet wurde, hatten sie in einem Dosisbereich von 4,0–5,9 mg DPH/kg eine signifikant (P<0,05) niedrigere Serumkonzentration als Männer. Dieser Unterschied weist auf geschlechtsspezifische, vielleicht hormonelle Einflüsse hin.