Surgical strategies for supra- and infratentorially grown occipital meningeomas.

BACKGROUND: Extensive tentorial meningeomas which are growing supra- and infratentorially are a surgical challenge, and a distinct surgical strategy is required for good results. PATIENTS: 3 patients, 2 with asymptomatic tumor and 1 with signs of increased intracranial pressure and visual disorder underwent microsurgery. RESULTS: In 2 patients, the semi-sitting position was taken. A lateralized occipital/suboccipital craniotomy with exposure of the confluens sinuum, transverse and superior sagittal sinus was performed. First, the dura was opened infratentorially allowing good cerebrospinal fluid (CSF) release. In a second step the dura was opened supratentorially sparing the sinus. The tumor was then removed completely without brain swelling or significant venous bleeding. One patient underwent surgery in prone position. A unilateral occipital/suboccipital craniotomy with exposure of the confluens sinuum and the ipsilateral transverse sinus was made. The dura was opened supratentorially. A resulting occipital lobe swelling made enlargement of the craniotomy and additional infratentorial dura opening necessary. All patients recovered well without postoperative morbidity. Complete tumor resection was confirmed by early postoperative MRI. CONCLUSION: The authors recommend a semi-sitting position (less venous bleeding, less brain swelling) and a lateralized occipital and suboccipital craniotomy for optimal control of the venous sinuses. Opening of the dura should start infratentorially to allow for CSF drainage and brain relaxation but should be combined with a sinus sparing supratentorial dura opening for adequate visualization and total meningioma removal.

DNA immunisation with minimalistic expression constructs.

The low efficacy obtained in large animals makes plasmid-based DNA vaccines commercially unviable. Another concern is the presence of antibiotic resistance markers on virtually all conventional plasmids. Here we describe the use of minimalistic, immunogenically defined gene expression (MIDGE) vectors for DNA vaccination. MIDGE are linear, covalently-closed vectors containing all the essential information for gene expression and none of the non-essential and potentially dangerous plasmid backbone sequences. MIDGE vectors can also be chemically modified on both ends at defined positions allowing targeting of the DNA to specific cell types or cellular compartments. Immunisation of mice with simple and end-modified MIDGE vectors showed that they are efficacious tools to generate and/or manipulate antigen-specific immune responses.

Coagulopathy and outcome in patients with chronic subdural haematoma.

OBJECTIVE: The coincidence of coagulatopathy and chronic subdural haematoma (CSH) requires correction of coagulation to facilitate surgery. We investigated the correlation between coagulopathy and outcome in CSH patients. MATERIAL AND METHODS: We analysed past medical history, surgical treatment and coagulation parameters of 114 patients. RESULTS: Coagulation disorders were found in 42%. Preoperative treatment with prothrombin complex concentrate was necessary in 14%. A significant difference (P < 0.05) of the preoperative level of platelets was found between recurrent CSH and non-recurrent group. Totally, we had to perform re-operations in 17.5%. Eighty-one patients presented with Glasgow coma scale (GCS) > or = 13. After surgery GCS was > or = 13 in n = 92. There was an improvement of GCS in 46 cases, 61 patients maintained GCS score levels. Outcome was significantly worse in the alcoholic group (P < 0.001), and in the recurrent group (P < 0.05). In patients with substitution of coagulation factors, outcome was worse in the group with post-operative substitution only (P < 0.05). CONCLUSION: In CSH, the coagulation parameters and a subtle correction of coagulation are of special interest, regarding the worse outcome in patients with recurrent CSH and in those requiring post-operative substitution.

DNA vaccination with linear minimalistic (MIDGE) vectors confers protection against Leishmania major infection in mice.

Immunization protocols based on priming with plasmid DNA and boosting with recombinants of vaccinia virus (rVV) encoding the same antigen offer great promise for the prevention and treatment of many parasitic and viral infections for which conventional vaccination has little or no effect. To overcome some of the potential problems associated to the use of plasmids, we have developed minimalistic, immunogenically defined, gene expression (MIDGE((R))) vectors. These linear vectors contain only the minimum sequence required for gene expression and can be chemically modified to increase the immune response. Here, we demonstrate that MIDGE vectors coding for the LACK antigen confer a highly effective protection against Leishmania infection in susceptible Balb/c mice. Protection is achieved at lower doses of vector compared to conventional plasmids. This efficacy could be greatly improved by the addition of a nuclear localization signal (NLS) peptide to the end of the MIDGE vector. In fact, immunization with two doses of NLS-modified MIDGE conferred similar or even better protection than that achieved by priming with plasmid DNA followed by boosting with rVV. These results demonstrate that MIDGE vectors are a good alternative to plasmid and rVV for immunization.

Fatal liver failure associated with valproate therapy in a patient with Friedreich's disease: review of valproate hepatotoxicity in adults.

PURPOSE: Valproate (VPA)-associated hepatotoxicity is usually considered a problem of young children with polytherapy, mental retardation, and underlying metabolic defects. METHODS: An adult patient with fatal liver failure during treatment with VPA is presented, and a review of the literature on other adult patients is given. RESULTS: A 29-year-old female patient with Friedreich's ataxia and partial seizures with acute liver failure during VPA treatment is reported. The first symptoms of liver failure (i.e., apathy during febrile upper airway infection) occurred 2 months after starting VPA therapy. VPA was discontinued 10 days later on hospital admission, when she had hepatic encephalopathy and severe bleeding diathesis. The patient died of severe liver failure and bronchopneumonia after 4 weeks of supportive treatment. CONCLUSIONS: Twenty-six adult patients (>17 years) with VPA-associated fatal hepatotoxicity have been reported in the literature. Of the 26 adult patients, three were receiving VPA monotherapy. The age ranged between 17 and 62 years. The duration of VPA treatment before the first symptom varied between 7 days and 6 years. Twelve of the 26 affected adults had no underlying disease or a clearly nonmetabolic and non-hepatic disease. Therefore VPA-associated severe side effects also must be considered in adult patients without any evidence of a metabolic defect or underlying neurologic disease.

[Recommendations for blood studies and clinical monitoring in early detection of valproate-associated liver failure. Results of a consensus conferences 9 May - 11 May 1997 in Berlin]. / Empfehlungen zu Blutuntersuchungen und klinischer Uberwachung zur Früherkennung des Valproat-assoziierten Leberversagens. Ergebnisse einer Konsensus-Konferenz vom 9.5.-11.5.1997 in Berlin.

Valproate is a frequently used antiepileptic drug. It is associated with rare but serious adverse effects like liver failure. The first symptom is impairment of the patient's well being. Isolated changes of standard laboratory liver parameters are not reliable early indicators. Thus, according to the knowledge of today, prophylactic blood screening cannot predict complications. On the contrary, clinical symptoms are the most relevant indicators of impending complications, eventually supported by laboratory findings. An abrupt withdrawal of valproate and administering carnitin in parallel can interrupt the otherwise fatal course of the complication and induce a subsequent recovery. At a Consensus Conference the current knowledge about early detection and therapy of the valproate-induced serious hepatotoxicity was discussed. The results regarding recommended laboratory screening, as well as diagnostic and therapeutic strategies are reported.

Inhaled nitric oxide for avoidance of extracorporeal membrane oxygenation in the treatment of severe persistent pulmonary hypertension of the newborn.

UNLABELLED: Inhaled nitric oxide (NO) is thought to provide a noninvasive therapeutic alternative to extracorporeal membrane oxygenation (ECMO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN). OBJECTIVE: Since January 1993, we have studied inhalation of NO in PPHN patients meeting the ECMO criteria of our institution. We focused on the questions of whether or not the need for ECMO could be obviated and whether differences could be found between NO responders and nonresponders. DESIGN: NO gas was delivered via conventional IPPV ventilation in incrementally increasing concentrations from 20 to 80 ppm. PATIENTS: NO therapy was attempted in ten ECMO candidates with clinical and echocardiographical evidence of PPHN (mean OI 51.9, SD 10.4). RESULTS: At various NO levels (30-60 ppm), five patients showed a significant increase in mean PaO2 (range 32.9-85.9 mmHg). Improvement was transient in three patients (6-10 h) and prolonged in two others (54-80 h); in the latter cases, ECMO was avoided. Five patients did not respond at all to treatment. Responders and nonresponders differed in their mean respiratory tidal volume (8.9 vs 4.18 ml/kg, P <0.05). CONCLUSIONS: In our study, inhalation of NO obviated the necessity of ECMO therapy in only two out of ten PPHN patients. Thus, we would discourage any overoptimistic expectations about the effectiveness of NO therapy in PPHN until larger clinical trials have been performed.

Effects of inhibitors of enzymatic and cellular pH-regulating systems on central sympathetic chemosensitivity.

Previous studies in cats using isolated NaCl-CO2 perfusion of the lower brainstem demonstrated an intrinsic chemosensitivity of sympathoexcitatory bulbospinal neurones within the rostroventrolateral medulla (RVLM). In the present experiments, the effects of inhibitors of enzymatic and cellular systems, known to be involved in pH regulation, were investigated. Isolated perfusion of the lower brainstem with CO2-enriched solutions was performed and preganglionic sympathetic nerve activity (SNA) was recorded. Drugs were locally injected into the left RVLM with glass micropipettes. Perfusion of the RVLM with CO2-enriched solutions over a period of 15 s induced a marked increase in SNA. The magnitude of absolute changes in SNA during perfusion depended on the level of basal SNA before perfusion. Microinjections of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and acetazolamide (ACZ) induced a marked rise in basal SNA, whereas diethylpyrocarbonate (DEPC) and ethylisopropylamiloride (EIPA) had no significant effect on basal SNA. After application of DIDS and DEPC, the peak change in SNA due to perfusion of the RVLM with CO2-enriched solutions was slightly diminished. Furthermore, neither ACZ nor EIPA produced any significant influence on the slope, peak change and time course of the increase in SNA compared with control perfusions. We conclude that the enzymatic and cellular carrier systems tested in this study are not or only slightly involved in central sympathetic chemosensitivity.

Changes in medullary extracellular pH, sympathetic and phrenic nerve activity during brainstem perfusion with CO2 enriched solutions.

Measurements are presented of sympathetic nerve activity (SNA), phrenic nerve activity (PNA), and local extracellular pH (ECF pH) within the rostral ventrolateral medulla (RVLM) in response to perfusions of the RVLM with CO2-enriched saline. Experiments were performed on cats anaesthetized with chloralose. The ventrolateral medullary surface was exposed, and a catheter was placed in the left vertebral artery from the axilla to allow perfusion of the RVLM. Baroreceptor and peripheral chemoreceptor denervations were performed by cutting the vagal, aortic and carotid sinus nerves. The activities of the renal and the phrenic nerve were recorded, in some experiments in parallel with the cardiac nerve. Recordings of the pH were done with ion-sensitive theta-microelectrodes. A linear relationship between the CO2 concentration of the perfusate and the evoked changes in ECF pH was found. The ECF pH did not change systematically in one or the other direction within depths between 1 and 3 mm below the surface of the medulla. The various patterns of interaction of ECF pH, SNA, and PNA are described in detail. Phrenic nerve response to perfusions was very variable; a more prolonged increase in amplitude of phasic discharges compared to the duration of changes in SNA and ECF pH was the most frequent finding, but non-phasic tonic activation and complete silence were also seen during perfusions. SNA could also deviate from ECF pH both with regard to its latency and to its time course in response to perfusions. Therefore, this study provides further evidence for deviations of cardiorespiratory adaptation from ECF pH, corroborating the notion that this parameter is not the decisive one for central chemoreception.

[Adenosine triphosphate for supraventricular tachycardia in newborns and suckling infants]. / Adenosintriphosphate bei supraventrikulären Tachykardien im Neugeborenen- und Säuglingsalter.

A previously healthy and normally developing 12-day-old female suddenly became restless and developed cold sweats, tachypnoea and tachycardia (300 beats/min). Neither electrocardiogram nor echocardiogram showed evidence of any cardiac defect. Carotid sinus massage and other vagus-stimulating manoeuvres, undertaken because paroxysmal supraventricular tachycardia (PSVT) was suspected, were unsuccessful. Before rapid digitalization, adenosine triphosphate was administered (0.1 mg/kg intravenously). Sinus rhythm was restored within about 60 s. Despite further treatment with digoxin and verapamil (4 mg/kg.d), further episodes of PSVT occurred, each again responding to ATP (0.1 to 0.3 mg/kg). There were no side effects. After 24-hour Holter ECG monitoring had revealed Wolff-Parkinson-White syndrome as cause of the PSVT, propafenone was administered (15 mg/kg daily) and has prevented further recurrence of the tachycardia.

Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities.

Since our last report on valproate (VPA)-related hepatotoxicity in 1988, 8 other children have died of VPA-associated liver failure in Germany and Switzerland. We compared the clinical course of these children with that of 6 children with a reversible outcome of severe hepatotoxicity related to VPA. Thirty-five percent of patients with fatal liver failure were normally developed, 23.5% were receiving VPA monotherapy, and 35.3% were aged < or = 2 years. The initial clinical symptoms of VPA-related hepatotoxicity were nausea, vomiting, apathy or coma, and increasing seizures in more than 50% of patients, in combination with febrile infections at onset of symptoms. As compared with the series of German patients reported in 1988, one third of the fatalities occurred after the first 6 months of therapy as compared with 6% in the 1988 series. Clinical symptoms and laboratory findings were the same in patients with reversible and with fatal outcome. Early or immediate withdrawal of VPA after the first signs of VPA-associated hepatotoxicity may be responsible for the increased number of children who recovered after VPA-related severe liver failure. The pathogenesis of liver failure during VPA treatment remains unknown; metabolic defects and cofactors such as polypharmacy or infections have become increasingly likely to contribute by depleting intracellular CoA. Worldwide, 132 patients have died of VPA-associated liver failure and/or pancreatitis. Because a group at risk for fatalities with VPA cannot be defined precisely, patients treated with VPA and their families must be made well aware of the clinical symptoms of hepatotoxicity such as apathy, vomiting, or increased seizure frequency, especially in the presence of febrile infections. Laboratory tests and clinical controls during the first 6 months of therapy should not be neglected.

Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity.

We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.5 M i.v.). Both respiratory and isocapnic metabolic acidosis induced a decrease in local extracellular pH, measured directly with pH-sensitive microelectrodes within medulla region containing sympathoexcitatory bulbospinal neurons. The magnitude of changes in medullary pH was independent of the way systemic acidosis was generated. Despite uniformity of changes in local medullary extracellular pH due to systemic respiratory or isocapnic metabolic acidosis, different responses were observed in preganglionic SNA. Isocapnic metabolic acidosis resulted in a slight increase in SNA, averaging 6.4% per 0.05 systemic pH unit decrease. In contrast, respiratory acidosis induced by decreasing artificial ventilation produced a more pronounced increase of SNA, reaching peak changes of approximately 70% compared with control level with normal blood gases, an average increase of 13% per 0.05 systemic pH unit decrease. We conclude that systemic CO2 and H+ concentrations represent different stimuli to sympathetic nervous system. Despite similar changes of local extracellular pH within rostral ventrolateral medulla during systemic acidosis, different responses of SNA suggest other sites or as yet unknown additional effects of CO2 as being responsible for excitation of sympathetic activity.

Historical development of current concepts on central chemosensitivity.

The history of concepts on the mechanism of central chemosensitivity is reviewed with special emphasis on ideas that have remained valid or stimulating until today. Early physiologists considered chemoreception to be a property of respiratory neurones in the brainstem (Pflüger 1868; Gesell 1926, 1949; Winterstein 1910, 1921, 1956). It has not been elucidated by which mechanism acid/base disturbances cause cardiorespiratory adaption. The reaction theory focused on protons as being the decisive stimulus (Lehmann 1888, Winterstein 1921, Loeschcke 1982), but this issue can be adequately discussed only when the compartment where changes occur is taken into account (Jacobs 1920, Gesell 1940). Heymans and collaborators demonstrated in 1930 that chemoreception is not only possible by a central mechanism but also at the level of the peripheral chemoreceptors. Without solid evidence for such an assumption, the existence of specific 'receptors' for pH and/or pCO2 was postulated by von Euler and Söderberg in 1952. Several chemosensitive areas at the ventrolateral surface of the medulla oblongata were defined by Loeschcke and collaborators in a series of papers after 1958. Within these areas, however, a specific chemoreceptor has not been distinguished. On the other hand, a direct chemosensitivity of bulbospinal sympathoexcitatory neurones as an intrinsic property of these neurones has recently been demonstrated (Seller 1989). Therefore, coming back to the original concept of chemoreception as a function of central cardio-respiratory neurones appears to be the most promising path for future research.

[Nocturnal hypoglycemias and cortisol excretion in overnight urine]. / Nächtliche Hypoglykämien und die Cortisolausscheidung im Nachturin.

In 20 juvenile diabetic inpatients the relationship between nocturnal hypoglycemia and overnight urinary cortisol excretion was studied. Cortisol was expressed as absolute quantity per kg body weight because the cortisol/creatinine ratio does not always yield reliable results in diabetic patients. Comparison between different patients yielded no significant difference between posthypoglycemic and non-posthypoglycemic cortisol values. Testing the difference between urinary cortisol excretion in posthypoglycemic and non-posthypoglycemic urine samples for every one of the patients intraindividually, however, a significant posthypoglycemic elevation was found. Posthypoglycemic cortisol response was irregular and variable not only in different patients, but also within the same patient. If a high excretion of cortisol is found in an overnight urine sample, it is very likely to be caused by nocturnal hypoglycemia. On the other hand it is impossible to exclude nocturnal hypoglycemia by normal urinary cortisol findings. Reactive hyperglycemia as described by Somogyi was seen only rarely in this study. It is concluded that even if a distortion by falsely high creatinine measurements in diabetics is ruled out, cortisol measurement in overnight urine samples cannot be used as easy routine method for the detection of nocturnal hypoglycemia.