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Gangliosides, i. e. sialic acid containing glycosphingolipids, constitute a major component of neuronal cells and are thought to be essential for brain function. UDP-glucose: ceramide glucosyl-transferase (Ugcg) catalyzes the initial step of glycosphingolipid (GSL) biosynthesis. A total deletion of the Ugcg-gene in mice led to embryonic lethality. In order to gain insight into the role of gangliosides in brain development and function, a cell specific disruption of Ugcg was performed.A cell specific disruption of Ugcg in mice was performed using the Cre/loxP-system. LoxP-flanked Ugcg-mice were generated and crossed with nestin-cre mice.The nestin-promoted gene deletion in neuronal cells was indicated by the absence of virtually all gangliosides already at stage E15.5. Shortly after birth mice showed dysfunction of cerebellum and peripheral nerves, associated with structural defects. Axon-branching of Purkinje cells was significantly reduced. In primary cultures of neurons dendritic complexity was clearly diminished, while pruning occurred. Myelin sheaths of peripheral nerves were broadened and focally severely disorganized. GSL deficiency also led to a downregulation of gene expression sets involved in brain development and homeostasis. Mice died approximately 3 weeks after birth.The pronounced neurologic symptoms in postnatal mice with neuronal specific deficiency of glucosylceramide synthesis demonstrate that GlcCer-derived GSL may not serve functions essential for early brain development. They are, however, required for neuron differentiation and brain maturation.

We present a case of death after first manifestation of generalised convulsive status epilepticus in a young man. A previously healthy 23-year-old man was admitted to our emergency department by ambulance service with approximately 20 min of generalised convulsive seizures. First line treatment in the emergency ward with benzodiazepines failed. The patient was cardiopulmonary stable until, after more than 30 min of status epilepticus, he developed tachycardia and became bradypnoeic. Intubation and ventilation was performed and anticonvulsive treatment was escalated with thiopental. Fifteen minutes later he developed ventricular fibrillation. CPR was started. The patient became asystolic after 90 min CPR following the ILCOR (International Liaison Committee on Resuscitation) Instructions. CPR was continued for another 30 min without success. The patient died after 120 min of maximal efforts. Autopsy and toxicology were performed, neuropathologic examination showed general brain edema and neuronal cell loss in purkinje cell layers of the cerebellum and olive knots which may be the consequence of generalised convulsive status epilepticus. We conclude: status epilepticus becomes refractory in approximately 30 % of cases. Until now, there are no randomised trials on the optimal treatment of refractory status epilepticus. Better treatment algorithms are urgently needed.

Three American Staffordshire Terriers were presented with gait abnormalities and loss of balance at the age of 4.5 (female) and 6 years (2 males). The onset varied between 3 and 5 years of age and the clinical signs were slowly progressive. The neurological examination revealed symmetrical generalized cerebellar ataxia with hypermetria, stiffness, and loss of balance with no evidence of paresis. The menace reflex was decreased in one dog and absent in another. A positional nystagmus was found in two dogs. The dogs were euthanized and a histopathological examination of each brain was performed. Pathological changes were confined to the cerebellum. The main finding was loss of Purkinje cells, as well as depletion of granular cell bodies and shrinkage of the granular and molecular cell layer. These findings are consistent with cerebellar cortical abiotrophy. A genetic basis is supposed, but the mode of inheritance is not determined yet. In contrast to some spinocerebellar ataxias in humans, the cause of Purkinje cell degeneration in cerebellar cortical abiotrophy of dogs is not known.

Paraneoplastic cerebellar degeneration is a rare disorder caused likely by autoimmune mechanisms in malignant oncologic diseases, and the most common tumors are ovarian, breast, lung cancer, and m. Hodgkin. An immune reaction is supposed to be directed against identical antigens of cerebellum and tumor, and paraneoplastic antibodies called anti-Yo, anti-Hu, anti-Ri, or anti-Tr are often detected in blood and cerebrospinal fluid. The course of paraneoplastic cerebellar degeneration as a complication of ovarian cancer is described. The relationship between the malignancy and pathologic changes in cerebellum was confirmed by positive immunohistochemical and immunofluorescence reaction between a patient's anti-Yo-positive serum and her own Purkinje's and ovarian cancer cells.

Case Report on a Breast Cancer Patient: A description of medical history, diagnosis and therapy of a patient with breast cancer is presented. The patient showed primary symptoms of vertigo and truncal and gait ataxia. The cause of this cerebellar disorder was a paraneoplastic cerebellar degeneration (PCD) characterized by anti-Purkinje cell antibodies (anti-Yo) directed against specific epitops shared by Purkinje and tumour cells. The presence of these antibodies in some patients suggests an autoimmune mechanism, although their role in pathogenesis has not been established. Usually malignancies of the breast and the ovaries are associated with anti-Yo positive PCD. The intensive search for the underlying neoplasma led to the identification of a malignant tumour of the right breast. Tumour excision of subsequent immunosuppressive treatment resulted in a progression of PCD. Antibody titers remained nearly unchanged during the course of the disease.

The rare case of a paraneoplastic, cerebellar degeneration is reported. In addition to the valuable early diagnosis of tumor disease, this paraneoplastic occurrence can also lead to false diagnoses in regard to both the underlying disease and the staging of the tumor. In the cases of known tumor disease, the assumption of cerebral metastasis is also possible.

The effects of the new antiarrhythmic drug AWD-G256 (1) were investigated by clinical electrophysiology (His bundle electrography, programmed electrical stimulation) in 19 patients with supraventricular tachycardias but without structural heart disease. In a maximal dosage of 0.45 mg/kg body mass 1 only minimally affects electrophysiological parameters of the impulse formation and conduction. At this time the therapeutic value of 1 is not clear.

A case of Ehlers-Danlos syndrome is reported, which was associated with mental retardation and early infantile autism. The patient died at the age of 19 by ectasy of the stomach as the result of extreme aerophagy causing a megacolon and by compression so finally resulting in a mechanical ileus. Investigation of the cerebellum revealed a significant rarefication and diminuation of the Purkinjè cells as well as the cells of the stratum granulare in the lobuli VI and VII, obviously due to a genetically determined malformation.

In the cerebellar cortex of the Rhesus monkey and the cat, the supraganglionic plexus in the molecular layer exhibits regional differences. The plexus is very well developed in the vermal parts of the anterior lobe, but only poorly developed in the nodulofloccular lobe. Most of the fibers of this plexus are myelinated parallel fibers, which synapse in the typical manner with dendritic thorns of Purkinje cells. Only very few fibers of this plexus are recurrent collaterals of Purkinje cells. Their distribution throughout the cerebellar cortex does not display regional differences. These findings agree with physiological data on the disinhibition of Purkinje cells in different parts of the cerebellar cortex.

Neurotoxic action of methylchloride was reported by various authors. As this solvent is widely used in chemical industry the morphological changes in the CNS of guinea pigs due to methylchloride intoxication were comparatively studied by light- and electron-microscopy.19 guinea pigs of both sexes (body weight 300-600 g) were individually exposed to inhalation of methylchloride mixed to normal breathed air in a 2 Vol.-% amount in a pressurised vessel of 20,000 cm3 volume (details on the experimental arrangement see VOLK 1973) for each 10 min 6 times a week. 3 control animals were fed like the experimental animals and exposed to normal breathing air for the same time in the pressurised vessel. The experimental period varied between 7 and 70 days, the number of inhalations was between 6 and 61. At the end of the experiment the animals were sacrificed by perfusion with 3% buffered glutaraldehyde under Thiogenal anesthesia. For light microscopy paraffin sections were prepared from tissue samples of the cerebrum, cerebellum, brain stem, mesencephalon, spinal medulla and spinal ganglia (stainings: HE; Turnbull's blue; Nissl; Klüver-Barrera; Mallory; Bodian and Kossa). For electron microscopy tissue blocks of the cortex, corpus callosum, striatum, mesencephalon and cerebellum as well as of spinal medulla and spinal ganglia were postfixed in 1% OsO4 and embedded in Araldit in the common way.Clinical observations--9 animals showed normal behaviour after 32 inhalations in 37 days.--6 animals displayed staggering, atactic moving of the head, retardation in spontaneous reactions and mobility. Ataxia and paresis of the hind legs occurred earliest after 17 inhalations. 4 animals showed all these symptoms only after 25 days. Morphological findings: Macroscopy: Occurrence of necroses in the cerebellar cortex was mainly observed in the lower part of the vermis; pressings of tissue in the occipital foramen, tissue swellings around the aqueduct and consecutive enlargement of the lateral ventricles occurred. Light microscopy: Changes in the Stratum granulosum in the lower part of the vermis as pyknosis of the cell nuclei and hydropic swelling of the cytoplasm (fig. 1a) were seen after 10 days. Focal necroses of the granular layer as well as "Status spongiosus" and edema occurred after 21 days (fig. 1b). In later phases these alterations were also present in other regions of the vermis and of the cerebellum, too. Furthermore, edema of the Lamina dissecans, hydropic swelling of the Bergmann's glia and marked edematous transformation of the molecular layer were observed. In this phase the hitherto intact Purkinje cells responded to the intoxication by homogenization of the cytoplasm and cell necroses. Electron microscopy: Initially an increase in density of the nuclear chromatin of the granular cells was observed associated with formation of homogeneous electron dense chromatin fragments which were finally released to the perikaryon (figs. 2a, 2b)...

Neuropathological investigations of CNS of two epileptic patients (a man and a woman), who had been treated over years with diphenylhydantoin, disclosed in both cases severe cerebellar atrophy, with almost complete loss of Purkinje cells. Hypoxic tissue alterations were found neither in cerebellum nor in cerebrum. Ultrastructural examination of formalin fixed tissue revealed in cytoplasm of degenerating Purkinje cells multilamellar structures similar to those reported by other authors, presumably consisting of proliferated cisternae of endoplasmic reticulum, degenerating mitochondria and "multilamellar cytoplasmic bodies". However, these findings are very probably not specific; they were detected also in Purkinje cells of a non-epileptic patient of the same age-group, suddenly deceased by car accident. Reversible cerebellar dysfunction is a common manifestation of acute phenytoin toxicity. However, further factors can influence the action of DPH, leading to chronic intoxication and irreversible cerebellar damage. A review of these factors is given. The periodic monitoring of serum DPH-concentration is emphasized.

A single dose of actinomycin was applied to young Wistar albino rats in the critical phase of their cerebellar development. The morphological alterations of the cerebellar cortex were studied by means of light and electron microscopy on several postnatal days. The cell types of the cerebellar cortex reacted in different ways toward the noxious substance according to their stage of development. The acute alterations consisted of an edematous reaction of the neuronal and glial perikarya (light degeneration) and a shrinkage of the neurons (dark degeneration). A massive intercellular edema and a rarefaction of glia cells as well as the Purkinje cell fibres proved to be the long-term damage. This pattern of the alteration was discussed regarding the chemodifferentiation of the cells of the cerebellar cortex, the onset of cerebellar function on day 14, and the establishment of a neuroglial functional unit.

The cortex cerebelli of the normal, adult rat was investigated fluorescence histochemically by means of the paraformaldehyde method according to FALCK and HILLARP (1962) for visualization of catecholamines and a modified ninhydrin-reaction for the demonstration of GABA (PFISTER and GORNE 1978), respectively. The Purkinje neurons were shown to display a considerable variability of the fluorescent GABA reaction product. Noradrenergic boutons were shown to be arranged mostly in a punctate manner around the somata of the Purkinje cells. The Purkinje cell pericarya would thus be under the inhibitory influence of cerebellar bascet neurons as well as of Locus coeruleus neurons.

The brain of a 21-year-old man with imbecility and spastic tetraplegia since early childhood showed a diffuse sclerosis of the cerebral white matter and symmetrical degeneration of the thalamus and olivocerebellar system. The spinal nerve roots as well as proximal branches of the spinal nerves were hypertrophic and there was seen a marked fibrosis with some onion-bulb formations of Schwann cells. In spite of a possible relation to an unknown infection at the age of 3 months this case could preferably be regarded as a peculiar form of the combined system degeneration in the early childhood, including the cerebral white matter and peripheral nerves. An uncle of the patient had died of a similar nervous disease at the age of 20 years.

The total number and the number of Purkinje cells per square millimeter of the surface of the cerebellar granular layer were measured in albino rats from two strains: Chbb-THOM-Wist and Han: SPRD. The total number of the Purkinje cells in the cerebellar vermian lobules L I and L X with the exception of cells in the lobules VIb + c did not differ significantly. Statistically significant differences were found between the individuals of the two rat strains and within single lobules of the cerebella concerning the cell density of Purkinje cells per square millimeter surface of the granular layer. The results suggest heterogeneity of the cerebellar cortex between cerebellar lobules and between albino rats derived from different strains.

We have examined the effect of chronic administration of phenytoin on Purkinje cells of cerebellum in adult mice. After daily intramuscular administration of phenytoin for a period of six months no difference in the number of Purkinje cells could be found between the treated and control animals.

Using the Purkinje cells of the cerebellum from 42 rapidly and 28 slowly dying patients, we tried to find a correlation between the premortal hypoxie in brain and the result of HBFP staining. We found four different stages of staining and discuss here the causes of staining and false results.

In order to investigate the fine structure of the cerebellar cortex of domestic ruminants, tissue specimen were taken of the Lingula, Declive, Nodulus, Lobus paramedianus and Flocculus of 30 cows, sheep, and goats. The following techniques were used: Luxol-Fast-Blue and Nisslstaining, Bodian and Golgi impregnation according to BUBENAITE and to KEMALI (1976). Electronenmicroscopically, differences between these species were seen only in the thickness of the three layers and in the size and topography of the 7 different cells and the fibres of the cerebellar cortex. In contrast to other species, soma and fibres of the Purkinjecells often contained numerous lamellar bodies. As in other animals the granular endoplasmic reticulum is arranged in form of nuclear caps.

1. GABA was demonstrated in rat brain in fluorescence histochemistry. The alteration by application of submaximal doses of drugs of the distribution and intensity of the transmitter fluorescence was studied in hippocampus and cerebellum. 2. Isonicotinic acid hydrazide and Penicillamine leads to a distinct grain formation and diminishing of the fluorescence product, normally appearing homogenous. These effects are considered to reflect an enzyme (GAD) inhibition. 3. By Cycloserine a distinct increase of the GABA fluorescence is effected, presumably by inhibiting GABA-transaminase-activity. 4. Chloropromazine causes diminishing, grain formation and dislocation as well of the fluorescent product, supposedly due to an affection of the membrane binding properties of GABA. 5. Hypotheses concerning the chemical events of the GABA-reaction are worded.

The authors deal with the phenomenon of dualism of pale and dark ganglion cells in general, the phenomenon which, since FLEMMING (1882), still remains an actual problem of neurohistology. They deal with Purkinje cells from a special aspect with the aim to demonstrate the dualism through various staining methods. They directed their attention also to the question of the influence of perfusion and immersion fixation and length of staining with luxol-fast-blue on the production of luxol-positive (chromophilic) Purkinje cells. The authors have found that these methodologic circumstances do not influence the production of luxol-positive Purkinje cells, so it can be hardly spoken about an artifact. Examinations with the labelled leucine have shown that the increased metabolic activity can be observed in those Purkinje cells which in HE-picture are seen as pale ones. In the dark Purkinje cells leucine granulations are located on the surface of plasmatic membrane and they follow to some distance the main dendrite of those cells. The microautoradiographic method evidences for the increased leucine metabolism of the pale Purkinje cells as well.

The cerebellar postnatal development of young rats (Wistar) was investigated, whose mothers were given a 12% (W/V) ethyl alcohol solution for 7 days before and during pregnancy. Besides weighing less at birth, the experimental animals had a slower postnatal linear growth and gained weight less rapidly. Histological examination of the cerebellum showed an inpeded histogenesis, which could be observed in the Purkinje cells up to the 10th postnatal day. Moreover, a thick layer of embryonal granular cells with numerous mitoses could still be seen in the experimental animals at 3 weeks of age. After 30 days there was no histological difference between the controls and experimental animals. Because the Purkinje cells in the developing cerebellum represent the units were ribosomes are most abundant, it seems appropriate to ask, whether the observed inhibition of histogenesis could derived from an impaired cerebral protein synthesis. Disturbance of organogenesis was observed in three experimental animals afflicted with an extreme internal hydrocephalus.

Reports in clinical literature about persistent terminal extrapyramidal hyperkinesis in neuroleptic long-term treated patients and speculation about demential brain decomposition in such cases give rise to support irreversible psychopharmacotoxical brain damage. Histopathological and animal experimental results in this question given up to this day are not in agreement with each other. Therefore an own chlorpromazine long-term experiment in rats is reported with special regard to biometric-statistical results.Experiments were performed in 36 adult albino rats of either sex, weighing 300-400 g, fed by a standard diet, receiving food and water ad libitum. The animals were divided into 3 groups of 12 animals accidentally. Group I received 15 mg/kg/die chlorpromazine per os by means of a throat probe, group II 10 mg/kg/die, group III was left untreated (controls). The experiment was carried out for 6 months, the animals were killed by perfusion of Bouin's solution 6-8 weeks after interruption of chlorpromazine application. 8 mum paraffin sections were stained by kresylviolet. After histological examination the material was investigated statistically. In the ncl. N. XII, ncl. N. VII, ncl, orig et term. N.V., ncl. cochlearis ant., ncl. vestibularis princeps, Oliva sup., and ncl. dentatus the glia/neurons ratio was stated by counting 200 cells, and in the formation reticularis 400 cells in each animal. The calculated differences in the glia/neurons ratio between the groups were evaluated for statistical significance by the chi2-test. In the ncl. dentatus, oliva sup., ncl, cochlearis ventr., and ncl, vestibularis glia cells and neurons were counted in a plane of 1.2 mm2, in the formatio reticularis and in homologuous parts of cerebellar stratum moleculare in a plane of 2.4 mm2. The differences between the mean values of the groups were verified for statistical significance by means of the t-test.In histological examination only 50% of the animals of group I showed a slight loss of neurons and increase of glia cells. Statistically however, significant increase of glia cells was found in the glia/neurons ratio all over the investigated area (rhombencephalic brain stem and cerebellum) and for the ncl. dentatus, the oliva sup., and the ncl. cochlearis ventr. especially (table 1, fig.3). This change in the glia/neurons ratio is caused by a tendency for decreasing of neurons and increasing of glia cells, too (table 2). In the nucleus dentatus the loss of neurons was found to be of high significance. These changes are supposed to be due to chlorpromazine action, and in this manner the experimental results speak for an irreversible psychopharmacotoxical brain damage.

The author refers about different staining of the Purkinje-cells with luxol-fast-blue, gallocyanin, thionin and toluidin blue, chrom-alum-hematoxylin-phloxin, impregnation according to Palmgren, lithium and iron-hematoxylin, combination of the staining with phloxin and the Palmgren-impregnation and about the different activity on the acid phosphatase. The phenomenon that in the same histological specimen the positive (dark, chromophile) and negative (light, chromophobe) cells are situated beside, is true for normal animals too, but the number of the dark Purkinje cells is conspicuous higher after stress situations (96-h. immobilisation, intermittent hypoxia). This finding interprets the author by the occurence of phospholipids by binding on the granulated endoplasmatic reticulum, but also as a property of the neuroplasm. The author emphasizes that the staining dualism "light -- dark" of the ganglion cells does not refer only to the ganglion cells of the spinal ganglions (et on some epithelial cells), but also on the Purkinje cells.

Animal experiments have shown that in the course of chromatolysis the nuclear sex chromatin of nerve cells of female mammals changes its customary location at the nucleolus and migrates to the nuclear membrane; moreover, in the nuclei of nerve cells of males there occur under similar conditions nuclear structures which resemble the sex chromatin. It was, therefore, thought of interest to see if similar findings also apply to human Purkinje-cells.The cerebellum of 100 female and 52 male corpses of various ages was examined. Paraffin sections, 2-5 mum thick, were stained with haemalumeosin and, after hydrolysis by hydrochloric acid, with cresyl violet of Schiff's reagent (Feulgen stain). In each cerebellum 100 Purkinje-cells, whose nuclei showed a well developed nucleolus and an obvious Barr body, were studied. In the cerebellum of 29 female corpses the cells examined showed a marked cytoplasmic chromatolysis; in the Purkinje-cells of the remaining 71 female, and of all the male corpses the stage of chromatolysis was classified according to the degree of dissolution of the Nissl bodies as "feeble", "marked", or as the stage of restitution, characterized by nuclear caps.The sex chromatin was seen as a, mainly, round and compact chromocenter with a maximal diameter of 0.6--1.6 mum. The larger Barr bodies were seen more frequently, if chromatolysis in the corresponding cells was marked. With increasing chromatolysis the Barr body, which usually occupies a perinucleolar location, tended to be found more often at or near the nuclear membrane. In the cerebellum of the males 17.4% of the Purkinje cells studied showed heteropyknotic nuclear structures which could not always be distinguished in size or in appearance from a sex chromatin. They occupied predominantly a perinuclear position. but with increasing chromatolysis they too were seen more frequently in a location which tended to be intermediary or near the nuclear membrane. Not infrequently the nuclei simultaneously presented a granular hyperchromatosis.The change in the location of the sex chromatin in the nucleus is considered to be associated with compensatory processes following chromatolysis. These in turn are accompanied by an intranuclear current of materials, such as RNA, towards the periphery of the nucleus, or by changed electric potentials which develop in the affected cells. The variations in size of the Barr body should be attributed to a variable condensation of the corresponding X-chromosome, rather than to polyploidy of the nerve cell nuclei. The sex chromatin-like chromocenters, which are seen in "male" Purkinje-cells in the course of chromatolysis, could be attributed to certain chromosomal segments which have a tendency to heterochromasia...

Light- and electron-microscopie studies were performed in glia cells and neurons of the cerebellum of 12-day-old rats until 48 following intraperitoneal application of 8 mg/kg 6-aminonicotinamide (6-AN), an antimetabolite of nicotinamide that inhibits the oxidative pentose-phosphate pathway. Particularly sensitive were the neuroblasts of the external granular layer. The migration of the neuroblasts was clearly reduced. Parts of the internal granular layer were damaged, while the Purkinje cells and astrocytes remained unchanged. Oligodendrocytes and astrocytes showed vacuolar degeneration. Swelling of the myelin sheath occurred in the form of a status spongiosus. 48 h after 6-AN injection some mitoses and phagocytic cells were found in the internal granular layer.