Biomedical subjects
Publications and source records attributed to T Dorn.
Fyodor Mihailovich Dostoievsky is considered one of the most important Russian authors of the nineteenth century. He suffered from epilepsy since childhood, which disease often was a theme in his novels. This paper describes Dostoievsky's life and examines the various epileptic protagonists appearing in his works. Finally, the author's own epilepsy and particularly its etiology are discussed.
In symptomatic epilepsies due to chromosomal aberrations, epileptogenesis may be either the direct consequence of deletion or duplication of a gene causing seizures or may have a more complex etiology caused by the disturbance of the interaction of several genes and environmental factors. We report on a brother and a sister with trisomy 19q13.3-->qter who present different epileptologic features and discuss epileptogenesis in this syndrome with respect to genes known to be located on the distal part of chromosome 19q. Both patients share mental retardation and several dysmorphic features. The boy was hypoxic at birth and showed an extremely delayed psychomotor development. The girl, however, had no significant neonatal problems, and her psychomotor development was better. Although the male had an abnormal EEG in childhood, his first partial seizures occurred only as late as at age 31 years. He subsequently became seizure-free with carbamazepine (CBZ). In contrast, the girl already suffered from absence-like seizures during childhood and became seizure-free under ethosuccimide (ESM). A photoparoxysmal response, however, is still visible in her EEG. The difference between the epileptologic features in these siblings points to epileptogenic mechanisms placed far downstream on the way from genotype to phenotype. The photoparoxysmal response--otherwise a facultative finding in genetically determined epilepsies--in the EEG of the sister, however, points to a closer relationship between the duplicated genes and epileptogenesis. The fact that genes encoding potassium channels are located on 19q13.3-q13.4 may also support the latter assumption.
A common symptom of epilepsies are recurrent unprovoked epileptic seizures. These can be classified as focal or generalised. Thus, we can speak of focal or generalised epilepsies. Considering the rest of the medical history and the results of EEG and brain imaging the terms idiopathic, symptomatic and cryptogenic (i.e. probably symptomatic) are used to further characterise an epilepsy in a single patient. These classification scheme which is used since the end of the eighties allows decision making in therapy and an estimation of prognosis. Due to progress in epileptology during the last decade a more sophisticated approach is required. Thus, semiology of the single seizure becomes more important. The evolution of signs and symptoms during a seizure tells us something about the seizure onset zone and the mode of seizure propagation. The knowledge of them is a prerequisite for surgical treatment. Furthermore, semiology of seizures should determine social implications of epilepsy by far more than the fact that they are epileptic. Beside seizure semiology we have to consider the underlying neuropathological condition since it determines treatment and prognosis. Epilepsy is a consequence of acquired or genetic brain diseases. In case of the latter it becomes more and more possible to characterise and diagnose the genetic syndromes and to understand their pathophysiology. In epileptology the exact knowledge of an underlying genetic disease is not only of scientific interest. Beside being a condition sine qua non for adequate genetic counselling it influences the choice of anti-epileptic drugs and determines whether surgical treatment is indicated. Thus genetics are an important part of comprehensive care in epilepsy.
Focal epileptic activity can be expected to influence distant brain areas via far reaching connections. To investigate such interactions the effects of focal epileptic activity on the metabolism of the brain were investigated in the rat cortex. Focal epileptic activity was induced by the application of penicillin onto the motor cortex. The focus, and to a lesser extent homotopic contralateral brain areas, showed an increase in the regional cerebral metabolic rate of glucose (rCMRGlc) as measured by [14C]deoxyglucose autoradiography. This focal hypermetabolism was accompanied by widespread hypometabolism lateral to the focus. The decrease of rCMRGlc occurred in somatosensory cortical areas but not in the motor cortex behind or in front of the focus, the perirhinal cortex or the occipital cortex. It was associated with an increase in metabolic rate in the ventrolateral, ventroposteromedial, ventroposterolateral and, in particular, posterior nuclei of the thalamus. It is hypothesized that the widespread reduction of rCMRGlc in the somatosensory cortical areas is due to inhibition via thalamic nuclei caused by activity in the motor cortex.
Under epileptic conditions, interictal epileptic events are followed by large inhibitions which prevent the transition to ictal discharges. In the present experiments the refractory period following interictal epileptic spikes was investigated in animal experiments. Interictal epileptic activity was elicited by application of penicillin onto the motor cortex of anesthetized rats. Interictal epileptic discharges were followed by an absolute refractory phase lasting 200-300 msec, in which no epileptic event could be elicited by epicortical stimulation. This was followed by a relative refractory period up to 900 msec after onset of the conditioning spike; spikes elicited with intervals between 300 and 900 msec were smaller than those with greater intervals and required higher stimulation intensities. This period ends by a sharp drop of threshold. In two-thirds of the experiments, spikes were favoured in intervals of 300-500 msec due to a sag of the threshold, which possibly indicates recurrent neuronal excitations. Stimulations with frequencies of about 1/sec favoured a transition from a pattern with spikes appearing in an irregular sequence every 2-3 sec, to a discharge pattern with spikes appearing with regular intervals of about 1 sec. This change of firing pattern was associated with a drop of the spike threshold. It is concluded that interictal epileptic events are followed by a refractory period comprising different components. Alterations of the neuronal inhibitions responsible for these refractory phases may be critical for the activity of the focus and may determine the transition from interictal to ictal discharges.
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Epileptic discharge patterns in an acute experimental model of epilepsy were analyzed. Epileptic foci were induced by epicortical application of penicillin on the rat motor cortex in vivo. Patterns with regular 1/s discharges, patterns with irregular discharges of about 0.5/s as well as compound patterns comprising discharges with intervals of about 300 ms could be differentiated by means of interval histograms and autocorrelation functions. These patterns occurred in an ordered sequence indicating that the different rhythms are activated by a progressive enlargement of the focus and duration of focal activity. The experiments suggest that different interictal discharge patterns can occur within the same brain regions and are not specific for a certain etiology; instead they seem to represent 'resonance' frequencies characteristic for the brain tissue which are disclosed under pathophysiological conditions.
Interneurons of rat motor cortex in vivo and of rat hippocampal slices were studied during penicillin-induced epileptic discharges. Synchronous with pyramidal cells, they showed transient depolarizations similar to paroxysmal depolarization shifts in pyramidal cells. The transient depolarizations were followed by hyperpolarizing or depolarizing afterpotentials lasting 600 to 1200 ms. During the transient depolarizations and the afterdepolarizations the interneurons discharged with increased frequency. This may contribute to the enlarged and prolonged synaptic inhibitions following interictal discharges in pyramidal cells.
Epileptic discharges were induced by superfusion of rat hippocampal slices with penicillin. Under these conditions the neurons generated paroxysmal depolarization shifts (PDS) after electrical stimulation of Schaffer collaterals. The PDS were followed by large afterhyperpolarizations lasting about 2 s. The mechanisms causing these afterhyperpolarizations were studied in CA1 pyramidal cells. A late component of the afterhyperpolarizations, which determined their overall duration, was blocked by intracellular application of EGTA and reduced by superfusion with 8-Br-cAMP. In the same neurons these drugs had a comparable effect on afterhyperpolarizations following depolarizing current injections; it was therefore concluded that the late component of the PDS afterhyperpolarizations was caused by a slow Ca2(+)-activated K+ current. An initial fast component of PDS afterhyperpolarizations, which peaked about 60 ms after PDS onset, was reduced by EGTA but not affected by 8-Br-cAMP suggesting that the fast Ca2(+)-activated K+ current also contributed to the PDS afterhyperpolarizations. Superfusion of the slice with the gamma-aminobutyric acid B receptor (GABAB) antagonists phaclofen or 5-aminovalerate reduced the amplitude of the afterhyperpolarizations during the first 1000 ms but did not affect the late Ca2(+)-dependent component, indicating that a GABAB-mediated K+ inhibitory postsynaptic potential (IPSP) contributed to the PDS afterhyperpolarization. Intracellular injection of Cl- revealed that an early part of the afterhyperpolarizations lasting about 500 ms was Cl(-)-dependent. This component was blocked by superfusion of the slices with bicuculline, suggesting that a GABAA-mediated Cl- IPSP contributed to the PDS afterhyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
This study investigated the responses to innocuous and noxious mechanical stimuli of joint mechanoreceptors with thick myelinated articular afferents (conduction velocities 21-65 m/sec) in the medial articular nerve of the cat's knee. In nine experiments, we examined whether acute arthritis would modify the discharge properties. The vast majority of the group II afferents were excited by gentle local stimuli and by movements in the working range of the knee. Although they encoded pressure and particular movement stimuli up to the noxious range, their responses were more closely related to the particular type of stimulus (e.g., a movement in a specific direction) than to its intensity (innocuous vs. noxious). In inflamed joints, the response patterns of group II units were similar with regard to local mechanical thresholds, thresholds for passive movements, and patterns of responses to passive movements. In both situations, most units had no resting activity. These results suggest that articular group II afferents do not play a significant role in nociception. Rather, they subserve proprioceptive functions such as deep pressure sensation and kinesthesia in normal as well as inflamed joints.
Penicillin-induced paroxysmal depolarization shifts (PDS) are followed by prolonged afterhyperpolarizations of about 2 seconds duration. Intracellular injection of EGTA blocked a late component of the afterhyperpolarizations; an early one lasting up to one second was only slightly reduced by EGTA. It is concluded that afterhyperpolarizations following penicillin-induced PDS comprise different components: an initial one lasting up to one second which is not Ca2+-dependent and a slow one lasting up to two seconds which is caused by a Ca2+-dependent K+ current.