The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease

We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. In conclusion: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism

Detection of the DCC gene product in normal and malignant colorectal tissues and its relation to a codon 201 mutation.

Protein expression of the putative tumour-suppressor gene DCC on chromosome 18q was evaluated in a panel of 16 matched colorectal cancer and normal colonic tissue samples together with DCC mRNA expression and allelic deletions (loss of heterozygosity, LOH). Determined by a polymerase chain reaction (PCR)-LOH assay, 12 of the 16 (75%) cases were informative with LOH occurring in 2 of the 12 cases. For DCC mRNA, transcripts could be detected in all analysed normal tissues (eight out of eight) by RT-PCR, whereas 6 of the 15 tumours were negative. DCC protein expression, investigated by immunohistochemistry using the monoclonal antibody 15041 A directed against the intracellular domain, was homogeneously positive in all normal tissue samples. In tumour tissues, no DCC protein was seen in 11 out of 16 samples (69%). For the DCC codon 201, we found a loss of a wild-type codon sequence caused by mutation or LOH in at least 8 out of 15 cases (53%) compared with the corresponding normal tissue. DCC protein expression was undetectable in eight of the nine tumours missing both wild-type codons. Only one of the five tumours with retained DCC protein expression had no detectable wild-type codon 201. In addition, 9 out of 15 normal tissue specimens were mutated in codon 201. In two out of three cases with homozygous wild-type codons in peripheral blood lymphocyte (PBL) DNA, mutations were already observed in the tumour adjacent normal colonic mucosa. We conclude that DCC immunostaining should be introduced in the clinicopathological routine because of its strong correlation with the known prognostic markers 18q LOH and mutation of codon 201

Adrenostatische Therapie mit Metyrapon und Aminoglutethimid beim ACTH-abhängigen Cushing-Syndrom

Bei zehn Patienten mit ACTH-abhängigem Cushing-Syndrom, vier mit ektopem Cushing-Syndrom und sechs mit M. Cushing, wurde retrospektiv die Wirksamkeit einer adrenostatischen Therapie mit Metyrapon (Metopiron®) und Aminoglutethimid (Orimeten®) untersucht. Unter Metyrapon allein (n = 5) sowie in Kombination mit Aminoglutethimid (n = 5) kam es bei allen Patienten zu einer dauerhaften Senkung der Serum-Cortisol-Konzentration. Die Beobachtungszeit betrug 2 Wochen bis 4 Jahre. Der angestrebte therapeutische Bereich von < 16 µg/dl wurde bei sieben Patienten erreicht. Im Verlauf der Therapie wurde ein Anstieg der mittleren Plasma-ACTH-Konzentration beobachtet; dabei kam es nicht zu einem »Escape« der Cortisol-Konzentration. Eine Einschränkung erfuhr die adrenostatische Therapie allein durch die Nebenwirkungen, die bei zwei Patienten zu einer Beendigung der Therapie führten. Folgerung: Die adrenostatische Therapie mit Metyrapon und Aminoglutethimid ist wirksam und praktikabel. Sie eignet sich nicht nur zur akuten Behandlung des floriden Cushing-Syndroms, sondern auch zur Langzeittherapie, wenn eine kurative Therapie nicht möglich ist.The adrenostatic effect of metyrapone (Metopiron®) and aminoglutethimide (Orimeten®) was assessed retrospectively in ten patients with ACTH-dependent Cushing's syndrome, four of them with the ectopic form. Five patients received metyrapone only, the other five both metyrapone and aminoglutethimide. Persistent lowering of the serum cortisol level was achieved in all, after an observation period of two weeks to four years. The intended therapeutic level of below 16 µg/100 ml was achieved in seven patients. In the course of treatment there was a rise in mean plasma ACTH concentration, but without an »escape« phenomenon. The adrenostatic treatment had to be limited, if at all, only because of side effects, which in two patients required that the drug administration be terminated. It is concluded that adrenostatic treatment with metyrapone and aminoglutethimide is effective and practical. It is suitable not only in the management of florid Cushing's syndrome, but also for long-term treatment when complete cure is not possible

Validation of computer-adaptive contrast sensitivity as a tool to assess visual impairment in multiple sclerosis patients

BACKGROUND: Impairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS). OBJECTIVE: To study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls. METHODS: We recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set. RESULTS: We identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129-373 s). The AULCSF had better test-retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01). CONCLUSION: High precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS

Diagnostik und Therapie asymptomatischer Nebennierentumoren

Bei 23 Frauen und neun Männern im mittleren Alter von 54 (25-73) Jahren wurde bei der Klärung anderer Beschwerden zufällig ein asymptomatischer Nebennierentumor entdeckt. In allen Fällen ließen sich die Tumoren computertomographisch darstellen. Achtmal waren sie beidseits lokalisiert, in je 12 Fällen rechts- oder linksseitig. Der durchschnittliche Tumordurchmesser betrug 3 (1-9) cm. Vier Tumoren (12,5 %) wiesen eine endokrine Aktivität auf (ein Phäochromozytom, drei cortisolproduzierende Tumoren). Acht Patienten wurden adrenalektomiert, dabei ergaben sich sechs Nebennierenadenome, ein benignes Phäochromozytom und ein Ganglioneurom. Eine Feinnadelbiopsie wurde bei zwei Patienten vorgenommen, der zytologische Befund war benigne. Computertomographische Verlaufskontrollen bei elf (34,4 %) der nicht-operierten Patienten 6-48 Monate (im Mittel 14 Monate) später zeigten bei keinem der Patienten eine Größenzunahme des Tumors. Daher erscheint es bei zufällig diagnostizierten Nebennierentumoren gerechtfertigt, zunächst einmal den Verlauf zu beobachten, da gutartige Prozesse offensichtlich weitaus häufiger sind als maligne. Bei einem Tumordurchmesser von mehr als 6 cm ist jedoch wegen des Malignitätsrisikos eine Adrenalektomie durchzuführen