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The purpose of this study was to examine the anaesthetic requirement of intrathecal midazolam in a dose-response fashion in isoflurane-anaesthetized, tracheostomized rats, and to evaluate the apnoeic threshold after each intrathecal midazolam dose. Intrathecal midazolam, 5, 10, 20, and 30 micrograms, was administered to 25 anaesthetized tracheotomized rats. Isoflurane MAC was determined by the tail-clamp method. The effect of intrathecal midazolam on the apnoeic threshold was evaluated, and light and electron microscopy studies were performed on cervical, thoracic and lumbar sections of the spinal cord to investigate possible midazolam-induced neurotoxic effects. Intrathecal midazolam 5, 10, 20 and 30 micrograms decreased isoflurane MAC by 16%, 31%, 42%, and 53% respectively (P < 0.05). The apnoeic threshold was increased by midazolam 5 micrograms (from a PaCO2 of 4.25 +/- 0.55 to 5.28 +/- 0.76 kPa, P < 0.05) when compared with baseline values, but not further by additional doses. Light and electron microscopy studies on sections taken from the spinal cord of four animals did not show any morphological changes suggestive of midazolam-induced neurotoxicity when compared with similar preparations obtained from controls. These data suggest that intrathecal midazolam possesses dose-dependent antinociceptive properties which, associated with the ceiling effect of the apnoeic threshold obtained at the lowest midazolam dose and the lack of neurotoxic effects, may potentiate inhalational anaesthesia without producing marked respiratory depression.

Epilepsy is one of the most common and serious neurological disorders, with up to 60 million people affected worldwide.1 Juvenile myoclonic epilepsy (JME) is a common familial form that accounts for 5–10% of all epilepsy cases.2 This form belongs to the idiopathic epilepsy group, due to the absence of detectable structural or metabolic abnormalities. Clinically, JME is mainly characterised by isolated myoclonic jerks on awakening that usually begin during adolescence. It is also highly drug-dependent, since a 90% recurrence is reported after interruption of pharmacological treatment.3 Studies on the incidence of epilepsy in relatives of probands with JME, as well as on twins, have provided strong evidence for a genetic contribution.4,5 Autosomal dominant, autosomal recessive, two locus, monogenic, and polygenic models of inheritance have been suggested.6 So far, three genes that are mutated in different forms of JME have been identified, namely CACNB4 ,7 GABRA1 ,8 and CLCN2 .9 In addition, two different susceptibility loci have been identified by linkage analysis. The first locus, termed EJM1 (OMIM 254770), is on the human leukocyte antigen region of chromosome 6p.10 Although no trait-causing mutation has yet been identified at this locus, association with a haplotype of the BRD2 gene has been recently reported.11 The second locus, termed EJM2 (OMIM 604827), is in the region of chromosome 15q that contains the gene coding for the α7-nicotinic acetylcholine receptor subunit. Genetic mapping of the EJM2 locus defined a 15.1 cM candidate region on chromosome 15q14, flanked by the D15S165 and D15S971 loci.6 Interestingly, this region includes the CX36 gene, which codes for the first connexin identified in neurons.12 Connexins are integral membrane proteins, encoded by a family of at least 20 genes in humans, which form the subunits of gap junction …

We report the case of a 61-year-old woman, who developed progressive paraparesia over a period of 8 months. Conventional X-rays of the thoracic spine showed an intra-spinal calcified lesion at T10. On CT-scan and MRI, the lesion appeared anterior to the cord, thus making a posterior approach hazardous. Total resection of this calcified meningioma was achieved through a right transthoracic transcorporeal approach, under close monitoring of the somatosensory evoked potentials. Despite a delayed pseudomeningocele formation requiring an additional thoracotomy, outcome after 7 years is excellent with no residual neurological deficit. No recurrence was seen on a CT-scan performed two years after the surgery. Calcified anterior meningiomas of the spine are rare lesions. Surgical outcome has been unfavorable for a long time in relation with posterior or postero-lateral approaches. Although anterior transthoracic procedures are routinely performed for extradural spinal lesions, this approach is rarely used for intradural lesions. A calcified anterior spinal thoracic meningioma should be managed like the more frequent calcified thoracic disk hernia, despite the increased risk of cerebrospinal fluid effusion requiring subsequent repair.

The Central Nervous System is the site of a wide variety of inflammatory and infectious diseases. Some disease entities have been in the focus of interest in recent years and progress has been achieved in our understanding of some chosen domains. We will review recent progress in our knowledge about transmissible spongiformes encephalopathies and AIDS-associated lesions, and briefly discuss cerebral vasculitis, granulomatous diseases and the most frequent infections by parasites.

Idiopathic polymyositis (IPM) and HIV polymyositis (HIV-PM) are considered to be related autoimmune diseases whose target is skeletal muscle. They have been associated to a T cell-mediated and MHC-I-restricted cytotoxic phenomenon, but both etiology and physiopathology remain incompletely understood. Their histological hallmarks are mononuclear leukocyte infiltrates as well as necrosis, degeneration, and regeneration of muscle fibers. In the present study, we have investigated the immunohistochemical expression of cell adhesion molecules, cytokines, and leukocyte surface antigens in biopsies of HIV-PM and IPM patients. The aim was to better define factors involved in lymphocyte recruitment and in inflammatory changes seen in PM. Notable upregulation of ICAM-1 and TNF-alpha was detected on capillary and venular endothelia and on inflammatory cells, whereas no significant VCAM-1 and ELAM-1 expression was present. LFA-1, the main ICAM-1 counter-receptor, was found to be highly expressed on lymphocytes and monocytes, especially at the vicinity of damaged fibers. The majority of infiltrating cells were CD8+CD45 RO-T cells, which are thought to have memory capacities. These findings suggest that in IPM and HIV-PM, enhanced ICAM-1 and LFA-1 expression possibly induced by TNF-alpha, may regulate the homing process of selected lymphocyte clones in muscle tissue. Lymphocyte proliferation and differentiation into memory subsets may further potentiate tissue-restricted homing capabilities.

After retinal branch vein occlusion (BVO), the arteriole crossing the occluded territories is often constricted. This constriction persists up to several weeks and is correlated with the development of extended territories of nonperfused capillaries. These are results of an investigation supporting the hypothesis that decrease in the production of nitric oxide (NO) accounts for the observed arteriolar constriction.Preretinal [NO] was measured using an NO microprobe in the anesthetized miniature pigs, before and during the first 4 hours after experimental branch vein occlusion. Modifications of arteriolar diameter were correlated to preretinal [NO] changes. The retinal arteriolar sensitivity to constitutive NO was checked by applying preretinal puff injections of nitro-L-arginine (L-NA) after both systemic hypoxia and branch vein occlusion.Two hours after branch vein occlusion there was a 73.7 +/- 4% decrease in preretinal [NO] and a simultaneous 25.4 +/- 3.4% decrease in the diameter of the arteriole in the affected territory. Both persisted for at least 4 hours after branch vein occlusion. Applying a puff of L-NA to an arteriole previously dilated by systemic hypoxia induced a vasoconstriction. However, no arteriolar constriction was observed when a puff was applied to an arteriole after branch vein occlusion.These results show that experimental branch vein occlusion induces in the affected retina an impairment in the release of constitutive NO and an arteriolar constriction, which, in turn, contributes to the development of hypoxia in tissue and neuronal swelling and death in the inner retina.

We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain.

We present hereby some results indicating that there is a significant decrease in the release of NO by the retina immediately after branch-venous occlusion (BVO).Using an NO microprobe we measured (NO) in the preretinal vitreous of miniature pigs before and two hours aRer bvo. Conventional and electronic microscopy were performed on the affected retina.At the retinal surface (NO) was reduced to 25% of the previous value two hours after BVO, at the same time significative oedema of the inner retina was observed.Immediately after BVO there is a significative decrease in the amount of NO released by the affected retina, parallel to the first evidences of an oedema of the inner retinal layers.

Study of early hystological lesions after experimental branch venous occlusion (BVO) in miniature pigs.The retina was taken 1, 2, 4, 6 and 8 hours after BVO with green argon laser for examination with conventional and electronic microscopy.1 hour after occlusion an extracellular focal oedema is observable in the ganglion cells optic nerve fibers and cells of inner plexiform layer; 2 hours after occlusion there is also an extracellular oedema of the external plexiform layer as intracellular oedema of the inner nuclear layer, 4 hours after occlusion the extracellular oedema is more diffuse especially in the ganglion cells, inner nuclear and optic nerve fibers layers. Cytoplasmic vacuolisation, nuclear pycnosis and ruptured cell membrane layers are observed; 8 hours after occlusion both intra and extracellular oedema are observable throughout the inner retina.After BVO histological lesions are found within one hour only following the occlusion, apoptosis and cell necrosis are present as soon as 4 hours after experimental BVO.

Creutzfeldt-Jakob disease (CJD), a subacute spongiform encephalopathy, is generally included among the group of human and animal diseases which is transmissible by a non-conventional agent, the prion, whose expression is conditioned by the host's genome. The process leading to neuropathological changes is still unknown. We report the neuropathological findings in 2 cases of the "panencephalopathic" variant of CJD, which is relatively common in Japan, but extremely rare in Europe and North America. When compared with the classical form this variant is characterized by a relatively long clinical course with persistent vegetative state and primary involvement of the white matter presenting in the form of demyelination and gemistocytic gliosis. The selective involvement of certain thalamic nuclei is a particular pathological feature in both our cases. There was practically complete neuronal loss with diffuse gliosis of the anteroventral (AV) and dorsomedial (DM) nuclei, while the neuronal loss in the pulvinar remained moderate: the other nuclei were apparently spared. A similar involvement of the thalamus has been reported in fatal familial insomnia, a recently described prion disease in which these lesions are predominant. A comparable distribution has also been observed in other degenerative neurological diseases such as Steele-Richardson-Olszewski disease, Alzheimer disease, and thalamic dementia (selective thalamic atrophy or with multisystemic degeneration). The AV and DM nuclei, commonly referred to as "limbic thalamus" represent phylogenetically the most recent thalamic structures and would appear to play an important role in the superior functions in man as memory, attention and awareness. In our cases thalamic lesions are selective, bilateral, and symmetric, not explained by Wallerian degeneration. These lesions may be due to the primary pathogenetic properties of the infectious agent. The rapid clinical evolution in a persistent vegetative state could be consequential to precocious and severe disfunction of the limbic thalamus.

It has recently been emphasised that a subset of patients with type 2 Gaucher disease die in the neonatal period. This report describes an Afghani family with two conceptuses having severe, prenatally detected Gaucher disease. Mutational analysis showed that the family carried a known complex allele which included mutations at amino acids L444P, A456P, and V460V. Although glucocerebrosidase RNA was present, an affected fetus had virtually no glucocerebrosidase cross reactive material on western analyses. The severe clinical course and pathology observed in these patients resemble that of the null allele Gaucher mouse, and suggest that the absence of glucocerebrosidase activity results in early death.

Pathogenic mechanisms in human cerebral malaria remain unclear. We reevaluate the role of cell-mediated immune mechanisms in the pathogenesis of this disease based on autopsy findings in a 34-year-old Caucasian male. Histologic examination of brain tissue showed typical features of severe malaria infection (sequestration of Plasmodium falciparum-infected erythrocytes in vessels, cerebral oedema, petechial lesions and Dürck granulomas). In addition to these classical changes, we found that leukocytes that stained positively in immunohistochemistry for CD68 and tumor necrosis factor-alpha (TNF) coexisted with infected erythrocytes in capillaries, whereas in venules the monocyte population outnumbered the erythrocytes. Notable expression of ICAM-1 on endothelial cell surface was detected by immunohistochemistry in vessels with sequestered cells but not in unaffected vessels. These changes are identical to those of the murine model of the disease, in which cell-mediated immune mechanisms and TNF have been implicated. In vitro, ICAM-1 has been shown to be a potential ligand for P. falciparum-infected erythrocytes. In malaria patients, high serum TNF levels, which have been detected in close correlation with disease severity, may thus favor adhesion to endothelial cells of either red or white blood cells via enhanced ICAM-1 expression. The present observations are further evidence for a role of cell-mediated immunity in the pathogenesis of human cerebral malaria.

A primary benign melanotic tumour was resected twice in the thoracic spinal cord of a 49-year-old woman. The patient had complained of low back pains, obstipation and mictional urgency for two years. She developed a partial Brown-Sequard's syndrome at th10-th12 level. The tumour showed the histological and immunohistochemical features of a meningeal melanocytoma. The following up was marked by tumoral seeding in the lumbosacral region and later in the cerebral hemispheres, which lead to death 4 years after the diagnosis. This is a survey of the clinical and morphological characteristics of meningeal melanocytoma and demonstrates the risk of secondary dissemination of this primary benign tumour.

We report the first case of lethal intracranial haemorrhage complicating a treatment by rt-PA in a patient presenting with a simultaneous staphylococcal septicemia with meningoencephalitis and an acute myocardial infarction with cardiogenic shock. The presence of microvascular lesions in the central nervous system seems to be important risk factor for intracranial haemorrhage and we recommend extreme caution in the use of thrombolytic treatment in septicemic patients with acute myocardial infarction, particularly when neurological symptoms are present.

The authors reports their experience of 5 cases of intra- and peri-aqueductal tumors. With the exception of 1 case, a subependymoma of the aqueduct discovered at autopsy in a 77 year old woman, the 4 other patients (2 females and 2 males) are relatively young (respectively 14, 23, 14 and 26) at the time when they presented with signs of chronically raised intracranial pressure due to a triventricular hydrocephalus. One patient presented with a partial Parinaud's sign, but the focal and long tract signs were conspicuously absent in the other patients. The diagnosis of a space occupying lesion in the tectum mesencephali or in the aqueduct could only be ascertained with the recent use of M.R.I. The radiological work-up of the cases suggest that theses lesions, presumably of glial origin, are very slowly growing tumors. Four patients have been treated for their symptomatic hydrocephalus, but no treatment of the tumor has been proposed, as the clinical state and the images remain remarkably stable. (Mean duration of follow up from the time of shunting = 3.7 years, extremes = 1.5-8 years). A review of the literature shows that not more than 48 cases of tumors of the aqueduct have been reported. Because of the small number of such observations, there are, until now, no precise informations on the management of such cases to decide if the patient will benefit of an open or stereotactic biopsy associated with radiotherapy or if one can rely on serial clinical and radiological examinations. Further information on the long term follow up is needed.

Purpose Study of early hystological lesions after experimental branch venous occlusion (BVO) in miniature pigs. Materials and methods The retina was taken 1, 2, 4, 6 and 8 hours after BVO with green argon laser for examination with conventional and electronic microscopy. Results 1 hour after occlusion an extracellular focal oedema is observable in the ganglion cells optic nerve fibers and cells of inner plexiform layer; 2 hours after occlusion there is also an extracellular oedema of the external plexiform layer as intracellular oedema of the inner nuclear layer, 4 hours after occlusion the extracellular oedema is more diffuse especially in the ganglion cells, inner nuclear and optic nerve fibers layers. Cytoplasmic vacuolisation, nuclear pycnosis and ruptured cell membrane layers are observed; 8 hours after occlusion both intra and extracellular oedema are observable throughout the inner retina. Conclusions After BVO histological lesions are found within one hour only following the occlusion, apoptosis and cell necrosis are present as soon as 4 hours after experimental BVO.

PURPOSE We present hereby some results indicating that there is a significant decrease in the release of NO by the retina immediately after branch-venous occlusion (BVO). METHODS Using an NO microprobe we measured (NO) in the preretinal vitreous of miniature pigs before and two hours aRer bvo. Conventional and electronic microscopy were performed on the affected retina. RESULTS At the retinal surface (NO) was reduced to 25% of the previous value two hours after BVO, at the same time significative oedema of the inner retina was observed. CONCLUSIONS Immediately after BVO there is a significative decrease in the amount of NO released by the affected retina, parallel to the first evidences of an oedema of the inner retinal layers.

The immunohistochemical distribution of the vitamin D-dependent calcium-binding protein (CaBP) was studied in the cerebellar vermis of 14 adult type (NIDDM) diabetic and 13 nondiabetic human subjects. In both groups, CaBP-immunoreactive material was found in Purkinje cells and in axons of the cortical white matter, but, when compared with controls, the positive structures had a significantly (P < 0.001) reduced volume density in 12 of the 14 diabetic subjects. The reduction of the volume density of CaBP-positive structures in diabetic subjects was not due to an overall reduced volume of the molecular layer or of the cortical white matter. These results complement previous reports of a reduction of CaBP levels in duodenum and kidney of diabetic subjects.

A series of 20 hemispheric tumors in children less than 16 years of age, over a period of 20 years, is presented. Among them, 8 were oligodendroglial tumors, a proportion well above the level reported in the literature. The World Health Organization (WHO) classification, which includes mixed oligoastrocytomas, in the oligodendrogliomas was used. This addition does not explain this unusually high proportion. Selection of cases and the correct histological diagnosis are probably important.

Full-contact, a sport which is becoming more and more popular in our society as a means of self-defence, is not without its hazards. We describe the case of a 32-year-old man who, shortly after an intensive practice match, presented symptoms consistent with cerebral damage which resulted in his death within three days. The main pathological findings were confined to the left internal carotid artery, which presented a dissecting aneurysm as a result of rupture of its intima with thrombosis of its lumen. The thrombus extended as far as the intracranial portion of the artery, resulting in massive cerebral infarction as cause of death. Furthermore, there were histological modifications of both main carotid arteries and their branches which suggested repeated microtraumatic events. The causal relation between the lesions observed and the practice of full-contact are discussed.

Amyloid deposits were observed in a prolactinoma accompanying an amenorrhea-galactorrhea syndrome. The amyloid showed typical fibrils that were grouped in compact bundles. The seven other cases described in the literature are reviewed; evidence is accumulating that this amyloid can be secreted by epithelial cells.

An unusually large Sertoli cell adenoma was detected in a patient with Morris syndrome and there is a description of the uncommon hormonal data found in this particular case which are not typical for this kind of neoplasia. The patient is alive and well at the present time which is now three years after surgical intervention.

After a review of the literature, personal observations of primary benign and malignant tumours of the liver, studied using laparoscopic biopsy are presented and the importance of this examination in the early diagnosis of primary hepatic tumours is stressed. This examination, particularly when associated with biopsy, is very useful since it reduces diagnosis time with little or no risk to the patient with a high percentage of positive results.

A case of disseminated mycosis with encephalitis unobserved in life is reported. A mycosis infection ought always be taken into consideration every time that a clinical impression of encephalitis, meningitis or cerebral abcess is reached. Criptococcosis, Histoplasmosis and Candidiasis may present as a meningitis, which the Nocardiasis and the Cladosporosis may appear as an intracranial abscess in the absence of significant lesions of other organs. Many deep mycosis prove to have characteristic lesions in other organs before affecting the Central Nervous System. Development therefore of neurological symptoms ought to make one think of a dissemination at CNS level. Finally Candidosis and Aspergillosis ought to be suspected in all cases of progressive general weakeness after an illness especially when treated with antibiotics, citotoxis drugs, or hormonal steroids. In many cases the neurological lesions represant a manifestation of terminal type in a subject with many more lesions than one would suspect at first.

Twelve cases of ganglioneuroblastoma of the brain, tumour rarely observed in infants and young adults, are documented. The macroscopic, histologic and biological features of this tumour are discussed and compared with those of the literature. The author proposes an histogenetic hypothesis, which takes into consideration the possible association of an underlying dysplastic condition, comparable to that observed in cases of phakomatosis. Attention is drawn to the diagnostic difficulties, especially in that which concerns the diagnosis on frozen sections.

Neuropathological changes were studied in a consecutive autopsy series of 135 cases, comprising 73% of all patients who died of AIDS in Switzerland between April 1981 and December 1987. Central nervous system involvement was found in 119 patients (88%), 19 of which had multiple concomitant intracerebral lesions. Among the non-viral opportunistic infections, encephalitis due to Toxoplasma gondii was most frequent and occurred in 35 patients (26%), followed by central nervous system infection with Cryptococcus neoformans, which was found in five patients (4%). Cytomegalovirus (CMV) encephalitis was present in 14 patients (10%). Disseminated microglial nodules without morphological or immunocytochemical evidence of CMV was encountered in 18 patients (13%). However, in all but two of these patients there was evidence of extracerebral CMV infection, suggesting that CMV was responsible for these nodular encephalitides. Nine patients (7%) had progressive multifocal leukoencephalopathy (PML); in five of these, demyelination was associated with extensive tissue destruction and cyst formation. HIV-associated encephalopathy was observed in 21 patients (16%) and showed two characteristic morphological patterns: progressive diffuse leukoencephalopathy (PDL) and multifocal giant cell encephalitis (MGCE). PDL was observed in 13 cases and characterized by diffuse pallor and gliosis of the cerebral and cerebellar white matter with scattered multinucleated giant cells, but without significant inflammatory response. MGCE was found in eight patients and characterized by clusters of numerous multinucleated giant cells, rod cells, macrophages, lymphocytic infiltrates and occasional necroses. In our view, PDL and MGCE represent the two opposite variants of HIV-induced encephalopathies, with overlapping intermediate manifestations.

A very early case of D.S.H. (Hereditary Spongy Degeneration of the central nervous system) is described: clinical examination, C.A.T.-Scan (computerized axial tomography), biopsy and autopsy. The case presented in a 3 weeks old girl as a "colic of early infancy". During the fourth week, sudden worsening took place with attacks of dyspnea, cyanosis and frothy sputum. Ultrasound showed an echogenic thalamus. Examination by C.A.T.-Scan showed pale areas in the mid-brain and the central nuclei on both sides suggesting cerebral lesions of circulatory origin. Despite a normal lumbar puncture, cerebral biopsy was performed to exclude a potentially treatable viral condition (herpetic encephalitis?). Death took place 24 hours later. No inflammatory or spongy degenerative changes compatible with D.S.H. were found at biopsy. At autopsy however, despite superimposed recent ischemic lesions, microscopy and electron microscopy were characteristic of Hereditary Spongy Degeneration of the C.N.S. Six previous cases of D.S.H. are reported in the literature (explored by C.A.T.-Scan and confirmed histologically), this being the first report of hypodensities in the brain stem and central nuclei. In conclusion, this case shows once more that C.A.T.-Scan can be a useful tool in this still little known condition.