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In spite of substantial advances in intensive care for extremely preterm babies, including continuous monitoring and minimal handling, prevention of intracerebral hemorrhage is not successful in some cases. Unless treated adequately, a progressive posthemorrhagical hydrocephalus leads to considerable impairment of neurological outcome. Several conservative treatment strategies have been published, but often fail to avoid a permanent ventriculoperitoneal shunt implantation with its possible complications.Our therapeutical regimen of posthemorrhagical hydrocephalus focussed on resolving the mismatch between production and resorption of intracerebral fluid (ICF) by direct lysis of intracranial hematoma and fast decrease of ICF protein concentration. To achieve this goal, we instilled repeated doses of recombinant human tissue plasminogen activator (rt-PA) and dexamethasone intraventricularly, generally via external ventricle drainage systems used also to relieve the elevated intracranial pressure.Relevant complications were not observed. Conservative management without shunt operation was only possible in one out of the treated patients.Controlled multicenter studies are needed for statistical assessment of treatment efficiency.

The aim of this study was to establish a novel model permitting repetitive analysis of osseous perfusion over a period of 33 days using the fluorescent microsphere technique. After implantation of two port systems into the right and left carotid artery in New Zealand rabbits (n = 3), fluorescent microspheres were injected into the left ventricle, while blood samples for reference probes were taken from the descending aorta. Using seven different fluorescently labeled microspheres, injections were repeatedly performed starting 3 days after implantation (t = 0) at days 1, 3, 5, 12, 19, 26, and 33. Osseous blood flow was semiquantitatively analyzed by counting the number of trapped microspheres within the bone sections performed through the distal femur condyle (n = 8) using a fluorescence microscope. Over the entire observation period of 33 days, intraindividual variance in the number of trapped microspheres was low while there were marked interindividual differences between animals. The mean osseous perfusion in the three animals evaluated so far remained constant over the observation period of 33 days. The present model is the first to allow repetitive analysis of osseous perfusion over an observation period of 33 days. Using this model, the role of regional osseous perfusion can be studied under conditions such as impaired bone healing following radiotherapy- and/or chemotherapy, implantation of biomaterials, and transplantation of bone.

Intraventricular administration of recombinant tissue plasminogen activator (rt-PA) is an experimental therapy to hasten the lysis of intraventricular hemorrhages. We report nine patients (7 male, 2 female, mean age 64a) with intracerebral hematoma with ventricular extension who were treated with intraventricular infusion of rt-PA (2-32 mg, mean dose 17 mg). In two patients, clinically significant bleeding complications were associated with the fibrinolytic therapy. In one of these patients, fibrinolytic therapy was stopped. Other complications could not be observed. In eight of all nine patients, a rapid and extensive reduction of the amount of intraventricular blood occurred. A persistent shunt became necessary in two patients. We conclude, that intraventricular fibrinolysis probably leads to a faster clearance of intraventricular blood. Despite of fibrinolytic treatment, a permanent shunt becomes necessary in some cases. Intraventricular fibrinolysis is a potentially hazardous therapy with the risks of bleeding complications and infection.

The therapeutic concept of local administration of opioids into the perimedullar and cerebrospinal fluid is the result of fundamental studies concerning the discovery and localization of specific binding sites. These studies provoked considerable clinical interest, because they suggested a non-destructive and fully reversible method. In our department we have been gathering experience with an implantable pump system for various indications of chronic pain on a sample of 25 patients. The first implantation was performed in February 1987 and the latest included in this study in February 1991. The sample of patients consisted of two groups: (A) Chronic non-malignant pain (13 cases), (B) Chronic pain due to cancer (12 cases). We used two different pump devices: the gas-filled continuous infusion pump (Infusaid, Mod. 400) in 10 cases and the manually tractable micro pump (Cordis) in 15 cases. In 23 cases we decided in favour of an intraventricular drug administration, mainly because of the site of the pain; in each of these a ventricular catheter was placed in the frontal horn of the lateral ventricle. In the remaining two cases, the catheter was placed intraspinally, the catheter tip terminating at thoracic segments. Nine of the patients with cancer-related pain experienced from excellent to acceptable pain relief, as did also 10 patients with chronic non-malignant pain. Side effects were rare. Our findings also indicate that, in carefully selected patients, both malignant and non-malignant pain may be managed satisfactorily with this technique.

While shunt infections are regularly treated with intraventricular antibiotics, the validity of such an application in bacterial meningitis of other origin is controversial. We report two cases of partly successful treatment with intraventricular Ceftazidime (10-20 mg twice per week). One patient with pseudomonas aeruginosa meningitis who was treated as an out-patient for nearly two years died after an attempted withdrawal of the intraventricular treatment. In our experience, intraventricular application of antibiotics can be a part of the therapeutic regimen in all cases of chronic meningitis with problematic bacteria. Depending on the bacillus, Ceftazidime, Vancomycin or Netilmicin can be recommended for intrathecal application.

The influence of 500 microunits oxytocin as well as 50 micrunits lysine-vasopressin on hypothalamic self-stimulation rate after intraventricular application was studied. Oxytocin caused an increase and vasopressin a decrease in the self-stimulation rate.

A simple and rapid technique was introduced for the implantation of chronic metal cannulas into the rat brain lateral ventricle. This type of cannula can be used repeatedly during several weeks, and the animals can be housed in groups. Intracerebroventricular applications of substances can be given into non-restraint, conscious animals by free hand.

The authors describe the synthesis of a shorter-chained somatostatin analogue in which the ring size of the native molecule is largely preserved by incorporation of S-carboxymethyl-L-homocysteinamid and ring closure via its side-chain function. This synthesis involves the linkage of Boc-Phe-D-Trp-Lys[Z(pCl)]-Thr-Phe-Thr-Ser-OH to H-Hcy(CH2-CO-Lys[Z(oCl)]-Asn-Phe-OMe)-NH2 and subsequent azide cyclization. In contrast to somatostatin, the somatostatin analogue thus obtained produces, when applied intracerebroventricularly to rats, a decrease in the dopamine content of the striatum.

In a prospective, randomised study 35 patients suffering from lumbar vertebral disc herniation were given an intrathecal and peridural injection of 0.5 ml (= 10 mg) Triamcinolone hexacetonide. The postoperative course of the disorder was compared with that of 35 patients operated on the same manner, however, without medication. It was established that the intraoperative administration of Triamcinolonhexacetonid had no statistically significant influence on the results of the operations.

In order to determine the importance of opioid peptides in the central control of wakefulness, the synthetic analogue of Met-Enkephalin, FK 33-824 (d-Ala-2-Phe-Met-(O)-ol-Enkephalin) which is more resistant to enzymatic degradation, was perfused in increasing concentrations (20, 100, 200, and 400 micgrograms/ml) through the fourth cerebral ventricle of the conscious dog. In the EEG (Power-spectral density in continuous acquisition) high concentrations (200--400 micgrograms/ml) induce slowing (theta--delta) with overlying beta-activity. This was reflected in the animals behaviour resulting in a sleep-like state which in spite of the administration of high doses of the antagonist Naloxone (100 micrograms/kg i.v.) sustained for 12 hours. A simultaneously dose-related respiratory depression (drop in arterial pO2 and an increase in arterial pCO2) was reversed by Naloxone. It is concluded that the opioid peptide FK 33-824 induces EEG-slowing which is mediated by a subpopulation of opiate-binding sites, possibly the kappa-receptors. These receptors are different from binding sites mediating respiratory depression (micro-receptors) as they interact with the opiate-antagonist Naloxone.

Cryptococcal meningitis is a life-threatening disease. Headache, vomiting, cranial nerve symptoms and mental changes are the most common symptoms, but as many as 15% may have no symptoms referable to the CNS. For chemotherapy four drugs are available: namely amphotericin B, 5-fluorocytosine, miconazole and ketoconazole. Most cases have been treated by combination of amphotericin B and 5-fluorocytosine. The intrathecal administration of amphotericin B should be considered for patients who fail to respond to the usual intravenous therapy. The case is reported of a patient who died due to hydrocephalus, and the CSF-levels of the administered drugs are presented. Some pitfalls of therapy are discussed.

In 20 freely moving Wistar rats the influence of systemically and intraventricularly applied orotic acid derivatives on monosynaptically evoked field potentials registered in the dentate gyrus on the stimulation of the medial entorhinal cortex was investigated. Both, methylglucamine-orotate and tris-orotate led to an increase of the amplitude of the population spike. The slope function of the field EPSP, however, remained unchanged. The effect has been observed to begin 2 h after application and had a duration of 6-10 h. The data obtained in a monosynaptic pathway targeting on a brain structure which is known to play a crucial role in memory formation support earlier findings of a transient effect of orotic acid on cerebral excitation processes. An influence on mechanisms of spike generation or other postsynaptic membrane processes might be assumed.

The incorporation of 4.3-3H-L-leucine into total proteins of different Sommer's sectors of the rat hippocampus was studied. The labelling of the acid-soluble supernatant purified through anion exchanger, the specific activity of the proteins and the relative specific activity of the proteins following intraventricular and intraperitoneal application of 3H leucine were determined in vivo and, on hippocampal slices, in vitro. It has been consistently demonstrated in all experimental models that leucine is incorporated into total proteins of the hippocampal structures to a varying degree, the highest label being observed in the region "CA3". The findings seem to reflect differences in the protein synthesis of the individual hippocampal sectors. However, this conclusion was possible only on the basis of resuls taken as a whole, since each experimental model was afflicted with different methodical drawbacks limiting the interpretation of the results obtained.

To answer the questions of mode and site of action partly supplementary, partly new investigations with flupirtine (Katadolon) were carried out which are described below. The investigation for opiate receptor affinity of flupirtine in rat brain homogenate did not show any reduction in 3He-etorphine binding up to the highest concentration of flupirtine of 10(-5) mol/1. This result suggests that flupirtine either has a very low opiate receptor affinity or lacks it fully. Therefore the analgesic activity of flupirtine is not based on opiate mechanism. The intracerebroventricular and intrathecal administration of flupirtine and the other analgesics tested showed dose dependent analgesic activity in doses which, when applied systemically, did not cause any analgesia in rats. Thus these substances show cerebral or spinal analgesic activity. In relation to the effective doses (ED50 in micrograms/rat) flupirtine was of the same efficacy in both kinds of administration. Pethidine tested comparatively was found to be less potent by intrathecal than by intracerebroventricular application. On the other hand, morphine was weaker by intracerebroventricular than by intrathecal application. As in the experiments by oral administration, naloxone did not show any effect on the analgesic activity of flupirtine, neither by intracerebroventricular nor by intrathecal application. On the other hand, the analgesic effects of pethidine and morphine were completely suppressed by naloxone. These results demonstrate that the analgesic activity of flupirtine is not caused by the opiate mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Three patients with meningitis due to Pseudomonas aeruginosa (in one patient following a neurosurgical procedure and in two patients following severe head trauma with multiple skull bone fractures and liquorrhea) were treated with cefsulodin in combination with other antibiotics (aminoglycosides/acylureido penicillins). All of the patients were cured. Two patients received intraventricular administrations of aminoglycosides in addition to systemically applied antibiotics. After recurrence of pseudomonas meningitis in one patient in spite of the intraventricular application of an aminoglycoside, definite cure could only be obtained by additional intraventricular application of cefsulodin. The third patient was cured by systemic administration of cefsulodin and amikacin. The value of cefsulodin is discussed with reference to obtainable ventricular and lumbar CSF concentrations.

In five adult horned sheep long-term cerebro-spinal fluid pressure measurements were carried out before, during and after ten spinal-anaesthetics with the help of a canula which was fixed on the skull. In the lumbar subarachnoid space the pressure-course was recorded also, before and after the injection of local-anaesthetic. The following reproducible phenomena were found: Rapid pressure increase after injection, increase of cardio-respiratory oscillations and in two cases a sharp decrease of pressure after removal of the spinal needle. A connection between this and the cause of postural headache in man is postulated.

We report on a 81-year old patient who showed clinical signs of a shunt infection eight months after implantation of a ventriculo-atrial shunt system Heyer-Schulte. The reason was identified to be a massive infection with staphylococcus albus. Elimination of the infection was achieved by intravenous administration of fosfomycine and local instillation of gentamycin into the valve. The follow-up was uneventful for more than two years until the death of the patient in January 1987.

The authors describe the synthesis of beta-casomorphine-5 (Tyr-Pro-Phe-Pro-Gly) by segment condensation and stepwise building-up. Intracerebroventricular application of the pentapeptide to the rat produces a long-lasting analgesia against thermal stimuli (which can be inhibited by naloxone) and counteracts the extinction of a passive avoidance reaction for no less than 4 days following post-shock application. beta-Casomorphin-5 is very rapidly degraded by dipeptidylpeptidase IV; the degradation starts from the N-terminus giving dipeptides. The degradation products are competitive inhibitors of this enzyme.

Meningitis of the newborn is often accompanied by ventriculitis. This may be one of the reasons for the still unfavourable prognosis of neonatal meningitis. In a few cases we achieved sterile ventricular fluid with additional intraventricular application of antibiotics. An examination of ventricular fluids should be performed when there is the slightest suspicion of ventriculitis. Early institution of additional antibiotic therapy intraventricularly as well as some of the newer antibiotics (p.e. Cefotaxime) seem to produce better results. We observed the following complications of meningoventriculitis: hydrocephalus, porencephaly, and multicystic encephalopathy.

Tremor produced by intracerebral injection of carbachol. I. Susceptibility of different brain areas to carbachol Microinjections of carbachol into the lateral ventricle of rats caused tremor depending on dose. Intensity and duration of motor effects after injection of carbachol (30 mug/3 mul bilateral) into different brain areas were found to depend on localization: strongest tremor was elicited by injections into the nucleus caudatoputamen and cortex cerebri, moderate tremor by administration into the substantia nigra reticularis, globus pallidus and thalamic brain regions. Target areas of mean sensitivity were demonstrated in more rostral and caudal parts of the formatio reticularis. The injection of carbachol into the nucleus ruber, nucleus linearis and substantia nigra compacta brought about lowest tremor values. Ablation of the site of injection from the remaining brain abolished tremor induced by carbachol contrary to the tremor induced by oxotremorine.

The synthesis of somatostatin by linking together Boc-Ala-Gly-Cys(Bzl)-Lys(Z)-Asn-Phe-NHNH2 and H-Phe-Trp-Lys[Z(pCl)]-Thr-Phe-Thr-Ser-Cys(Bzl)-OBzl is described. The two partial sequences were obtained from segments which in general are also used in preparing somatostatin analogues. The synthesis of the partial sequences was optimized. The intracerebroventricular application of the somatostatin thus obtained to rats produced an increase of the dopamine and serotonin contents in the striatum. The results achieved were identical with those realized with standard somatostatin (Serono).

It is presented a autoradiographic method for microscopical detection of 3H-choline chloride activity after intraventricular application in freeze-dried and paraffin-embedded brain sections. The 10 micrometer thick sections are treated with diethyl ether and than exposed during 90 days above calcium chloride at 4 degree C using the sandwich technique (with stripping film). After separate film explanation and section staining the film and the brain sections are mounted together.

A new technique for intraventricular application of antibiotics by means of an indwelling catheter is described for the treatment of bacterial meningitis in the newborn. In cases of neonatal gram-negative meningitis with proven ventriculitis resistant to systemic therapy alone, a ventricular tap is performed. Through the needle an indwelling catheter is inserted into the right lateral ventricle. After removal of the needle the remaining catheter is used for obtaining ventricular fluid for diagnostic purposes as well as for direct intraventricular injection of antibiotics. This catheter can easily be inserted while the child is in the incubator in a neonatal intensive care unit, avoiding neurosurgery. Our present treatment procedure for neonatal meningitis is described.