Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study.

BACKGROUND: Pharmacologic and clinical risk factors for neuroleptic malignant syndrome have been suggested. High neuroleptic dose, rapid dosage increase, and parenteral administration were identified as risk factors in a case-control study; however, there are limited data regarding potential clinical risk factors. METHODS: To examine potential clinical risk factors, we conducted a case-control study, comparing 12 cases to 24 controls, all treated with neuroleptics at our center. In addition to examining previously postulated pharmacologic risk factors, we also assessed for presence of psychomotor agitation, confusion, disorganization, and catatonia. RESULTS: Significant differences were found between cases and controls for psychomotor agitation, confusion, disorganization, catatonia, mean and maximum neuroleptic dose, parenteral neuroleptic injections, neuroleptic dose increase within 5 days of the episode, magnitude of neuroleptic dose increase from initial dose, and extrapyramidal signs. CONCLUSIONS: This study demonstrated that psychopathological features such as psychomotor agitation, confusion, disorganized behavior, and catatonia may be risk factors for the neuroleptic malignant syndrome, in addition to pharmacologic risk factors and extrapyramidal signs, including akathisia. In clinical practice, careful monitoring for prodromal signs of neuroleptic malignant syndrome is required during neuroleptic treatment of patients with psychomotor agitation, confusion, and/or disorganization, while in the presence of catatonia these drugs should be avoided.

Somatostatin expression in TS16 mouse brain cultures.

Somatostatin expression in trisomy 16 mouse neuronal cultures has been studied to investigate the effects of the presence of an extra copy of the pre-pro-somatostatin (ppSS) gene on mouse chromosome 16. The immunoreactivity for somatostatin (SS) was considered in mixed cultures of neurons and glia cells and in neuron-enriched cultures as well as that for neuropeptide Y, glutamic acid decarboxylase, and gamma-enolase immunoreactivity the genes of which are not present on mouse chromosome 16. ppSS and pre-pro-neuropeptide Y (ppNPY) mRNA expression was evaluated and SS immunoreactivity in neurons analyzed by a morphometrical study. The extra copy of the ppSS gene resulted in a significantly increased level of the transcript in trisomic cultures, whereas the expression of the other neuropeptides did not differ. The absence of glial cells in these cultures reduced the number of SS-positive neurons making their number comparable in the trisomic and control cultures. Thus, in spite of higher expression of the ppSS mRNA in trisomic cultures, the determination of this peptidergic phenotype was influenced by the presence of neuroglial cells.

Clozapine effectiveness in a psychiatric service in Italy.

Clozapine was administered to 28 resistant schizophrenics at psychiatric services in Bologna. At 26 weeks 62% responded. Positive and negative symptoms improved, but decrease of negative symptoms partially depended upon improvement of positive and EPS. No cases of agranulocytosis were seen. Some drop-outs were related to difficulties with psychopathological improvement.

[Neuroleptic malignant syndrome. Case reports]. / Sindrome maligna da neurolettici. Una casistica.

Neuroleptic malignant syndrome is a serious adverse reaction of neuroleptic drug therapy, composed of mental status changes, muscular rigidity, hyperthermia, signs of autonomic instability and typical laboratory findings. The syndrome has received increased attention in the scientific literature since 1980; nevertheless some weighty issues regarding clinical symptoms, etiopathogenesis and treatment require additional studies. This paper presents 9 cases of neuroleptic malignant syndrome prospectively observed in 8 inpatients and 1 outpatient with different psychiatric diagnosis. Levenson's diagnostic criteria were fulfilled in 7 cases; the remaining two had slighter symptoms. So neuroleptic malignant syndrome is to be considered a rare but not unusual side effect of neuroleptics. The risk of syndrome doesn't seem to be correlated with chemical class, D2 receptor affinity and total dosage of neuroleptics; a key factor seems instead to be a quick loading rate of neuroleptics. Seven of 9 cases displayed severe changes in mental status (clouding of consciousness that varies from stupor to coma), violent psychomotor excitement and aggressiveness before the onset of the syndrome. Such clinical features seem themselves, in our experience, to be potential risk factors besides reason for an increase of neuroleptic dosage. Neuroleptic malignant syndrome usually is preceded by prodromal signs, the most important appearing the worsening of alterations in consciousness. Symptoms of neuroleptic malignant syndrome usually appear abruptly and in some cases with a dramatic course; they last, in cases with favourable outcome, a few days to two weeks from neuroleptic withdrawal; by far the worst outcome, instead, occurs if diagnosis and drug discontinuation are not carried out early. The first measure in the treatment of neuroleptic malignant syndrome consists of prompt discontinuation of all neuroleptic medications and other psychopharmacological cures, except for benzodiazepines, and institution of supportive therapy; such interventions can resolve the most of cases. Three patients treated with bromocriptine and/or dantrolene didn't display a different duration of clinical symptoms and rate of complications if compared to patients treated with supportive therapy only. Use of bromocriptine or dantrolene, or both, therefore should be considered as a second line of action. In four cases, neuroleptics were reintroduced within few days of recovery; low potency neuroleptics were employed, given low doses which gradually increased: in none of the 4 cases did the patients experience partial or complete recurrence of neuroleptic malignant syndrome.

[The prognostic significance of the extralaryngeal microscopic extension of a T3 glottic carcinoma]. / Significato prognostico dell'estensione microscopica extralaringea nel carcinoma T3 glottico.

Incidence of microscopic infiltration of the laryngeal framework, with or without extra-laryngeal extension, was studied retrospectively in a series of 63 patients treated surgically for glottic T3 carcinomas in order to establish prognostic values. The results of histopathological examination revealed neoplastic invasion of the fibro-cartilaginous skeleton in 46 of the patients examined and in half of these microscopic diffusion in peri-laryngeal tissue. As far as prognosis is concerned, there was a clear-cut correlation between a decrease in survival rates and a contemporaneous increase in the real extension of the neoplasia, even if microscopic. In fact the NED survival rate of confirmed T3 patients was 85% while in cases reclassified as pT4, it was 64% and 47% on the basis on the absence or presence of extra-laryngeal extension. With these observations it is possible to affirm that the major staging is also attributable to cases with initial infiltration of the "laryngeal framework" without an extensive extension toward peri-laryngeal tissue. As far as T recurrences are concerned, a high incidence of relapse of the neoplasia was observed principally in the cases with extra-cartilaginous diffusion. This observation may have a predictive role and therefore direct post-surgery follow-up as well as eventual complementary treatment.

A new approach to the histologic study of ovarian tumors by analytical morphometry.

In recent years, borderline epithelial tumors of the ovary have been investigated by morphometric techniques to allow for a differential diagnosis from benign and malignant neoplasms. In order to enhance this discriminant power, we have applied a new analytical procedure to the evaluation of the nuclear shape in epithelial ovarian tumors. Sixty nuclei of benign ovarian serous neoplasms, 60 nuclei of serous borderline tumors and 60 nuclei of serous carcinomas (18 cases in all) were examined using the software system SAM (Shape Analytical Morphometry). The morphometric procedure consisted of three different phases: (i) extraction of nuclear fundamental curve: this is a function curve giving the smoothing of the original contour by two parametric equations (separately for x and y values as dependent variables); (ii) evaluation of nuclear contour irregularities by Fourier analysis; (iii) evaluation of nuclear shape asymmetry by SAE (Shape Asymmetry Evaluator): this is the ratio between the length of a segment of a parabola interpolating the original curve points and a straight line joining its extremities for a 180 degrees barycentric rotation according 10 degrees steps. All the obtained independent parameters were submitted to statistical analysis. Nuclei of borderline tumors showed dimensional parameters which were intermediate between those of benign and malignant tumors. Both the asymmetry and the irregularities of nuclear contour were greatest in carcinomas.

Laryngeal intraepithelial neoplasia (LIN). An analytical morphometric approach.

Laryngeal Intraepithelial Neoplasia (LIN) is graded in 3 levels (LIN Grade I-II-III), corresponding to the classic aspects of mild, moderate and severe dysplasia-in situ carcinoma, on the basis of the number and position of mitoses and of the undifferentiated or atypical cells limited to the basal or extended to the intermediate or the superficial layers of epithelium. In order to reduce the subjective imprecision of these parameters we have applied not only traditional dimensional evaluators but also procedures of analytical morphometry to the nuclear shape. By using the software system S.A.M. (Shape Analytical Morphometry) we have examined fifty nuclei of the basal layer in LIN grade I, II and III, fifty nuclei in normal laryngeal mucosa and fifty nuclei in invasive carcinoma of the larynx (twenty-five cases in all). Normal and dysplastic nuclei did not show any dimensional differences, while the carcinomatous nuclei were significantly larger. An asymmetric distortion of the nuclear contour was noted in the moderate and severe dysplasia, but not in carcinomatous cells. Also the Fourier parameters, increased in severe dysplasia, decreased dramatically in carcinomatous cells which showed nuclei with minor contour irregularities than the normal cells. These findings outline the discriminative power of the analytical morphometry and suggest a possible correlation between nuclear shape and cell biology.

Morphometrical investigation of medulloblastoma nuclei by S.A.M. (Shape Analytical Morphometry) software system.

In order to characterize medulloblastomas and to get over the difficulties sometimes encountered in differential diagnosis, a double morphometric procedure has been applied to its nuclei. The first consisted of size measurements (maximum diameter, area and perimeter), the latter is represented by S.A.M. (Shape Analytical Morphometry) software-system specifically implemented to describe shape of biological structure by analytical parameters. Analytical and dimensional parameters submitted to Hotelling's multivariate discriminant analysis gave the best results when used together in convenient discriminant subsets, thereby allowing a good distinction between medulloblastoma in comparison with neuroblastoma, Ewing's tumor, lymphoblastic and lymphocytic lymphoma. These results underline the usefulness of morphometric characterization also for practical diagnostic purposes.

Variations of lymphocyte sub-populations in vulvar condylomata during therapy with beta-interferon.

Several experiences induced us to consider genital HPV infection as an expression of a local immunodeficiency. The aim of our study was to research the effect of immunotherapy on the lymphocyte subpopulations and Langerhans cells in vulvar condyloma. Twenty women with persistent vulvar condylomata, treated with 2,000,000 IU/die of beta-interferon for 15 days, were submitted to vulvar biopsy before and 2-5 months after medical treatment. The frozen sections obtained were assayed with the following monoclonal antibodies: OKT4 (T helper lymphocytes), OKT8 (T suppressor lymphocytes), OKB7 (B lymphocytes) and S-100 protein (Langerhans cells). Using a morphometric evaluation, the average number of both intraepithelial and stromal lymphocyte subsets and of the intraepithelial Langerhans cells was assessed. In all the biopsies preceding the medical treatment we found a low number of T helper lymphocytes both in the epithelium and stroma, with inversion of T4/T8 lymphocyte ratio and rare presence of Langerhans cells. In patients with a good therapeutic response (50-100% of condyloma reduction) we observed an increase in intraepithelial T4 lymphocytes and a decrease in both intraepithelial and stromal T8 lymphocytes. In cases with persistent disease after therapy, the histological pattern was similar to that observed in the first biopsy, with the exception of a significant increase in the average number of Langerhans cells. Our data correlate the clinical response to the immunotherapy with the histology of lymphocyte subsets in the vulvar condylomata. The increase in Langerhans cells observed in patients with negative response may be interpreted with a probable inability of these cells to promote the immune reaction.

Variations of lymphocyte sub-populations in vulvar condylomata during therapy with beta-interferon.

Several experiences induced us to consider genital HPV infection as an expression of a local immunodeficiency. The aim of our study was to research the effect of immunotherapy on the lymphocyte subpopulations and Langerhans cells in vulvar condyloma. Twenty women with persistent vulvar condylomata, treated with 2,000,000 IU/die of beta-interferon for 15 days, were submitted to vulvar biopsy before and 2-5 months after medical treatment. The frozen sections obtained were assayed with the following monoclonal antibodies: OKT 4 (T helper lymphocytes), OKT 8 (T suppressor lymphocytes), OKB 7 (B lymphocytes) and S-100 protein (Langerhans cells). Using a morphometric evaluation, the average number of both intraepithelial and stromal lymphocyte subsets and of the intraepithelial Langerhans cells was assessed. In all the biopsies preceeding the medical treatment we found a low number of T helper lymphocytes both in the epithelium and stroma, with inversion of T4/T8 lymphocyte ratio and rare presence of Langerhans cells. In patients with a good therapeutic response (50-100% of condyloma reduction) we observed an increase in intraepithelial T4 lymphocytes and a decrease in both intraepithelial and stromal T8 lymphocytes. In cases with persistent disease after therapy, the histological pattern was similar to that observed in the first biopsy, with the exception of a significant increase in the average number of Langerhans cells. Our data correlate the clinical response to the immunotherapy with the histology of lymphocyte subsets in the vulvar condylomata. The increase in Langerhans cells observed in patients with negative response may be interpreted with a probable inability of these cells to promote the immune reaction.

Multiparametric discrimination of serous ovarian tumors by analytical morphometry.

In order to enhance the discrimination power in the field of serous ovarian tumors, we applied the software system SAM (Shape Analytical Morphometry) to the analytic studies of biological forms. Besides the usual dimensional evaluations (perimeter, area, maximum diameter and shape index), this procedure permits the description of the nuclear form using analytical parameters: 1) extraction of nucleus fundamental curve; that is a functional curve giving the "smoothing" of the original contour by two parametric equations (separately for x and y values as independent variables); 2) evaluation of nuclei contour irregularities by Fourier analysis; 3) evaluation of shape asymmetry by SAE (Shape Asymmetry Evaluator); that is the ratio between the length of a segment of a parabola interpolating the original curve points, and a straight line joining its extremities for a 180 degrees barycentric rotation according 10 degrees steps. All parameters resulted to be independent and were submitted to multivariate discriminant analysis. We studied 180 nuclei from 18 cases of serous ovarian tumors, (6 benign, 6 borderline and 6 malignant tumors). With respect to the dimensional parameters, the application of analytical morphometry permitted us to reduce the minimum percentage error in the discrimination of the different classes. In fact, in the distinctions of benign and malignant nuclei, the minimum percentage error was 13.30%, against the 18.3% error when using dimensional morphometry. Furthermore, in the comparison of malignant and borderline nuclei there was a reduction of error from 23.3% to 22.5%, and in the comparison of benign and borderline nuclei, the error was reduced from 37.5% to 30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatoblastoma: a clinico-pathologic review.

Hepatoblastoma, the most common and peculiar tumor of the liver in infancy and childhood, has recently been the object of an international protocol of the European (SIOP) Histopathological Study Group in order to establish common anatomicoclinical criteria provided with therapeutic and prognostic significance. A general review of hepatoblastoma concerning its possible association with congenital anomalies, endocrine and metabolic disorders, as well as physical and laboratory data, macroscopic and histological patterns, is reported. The different histotypes of hepatoblastoma, represented by anaplastic, embryonal, fetal, mixed (epithelial and mesenchymal) and teratoid, are described, and hypothesis of the pathogenesis of this tumor is discussed, based upon immunohistochemical investigations.

Multivariate analysis of metastasis risk in laryngeal carcinoma. II. Immune response.

The presence of inflammatory reaction, plasma cells, and eosinophils in peritumoral connective tissue and in neoplastic stroma was evaluated with morphometrical method in 181 patients affected by laryngeal carcinoma. A logistic multiple regression model was applied making it with the use of an independent variable represented by the "infiltrating" or "expansive" types of tumor growth, in order to evaluate the probability of nodal metastatsis of each parameter. The results suggest an inverse correlationship between plasma cells and inflammatory infiltration and incidence of nodal metastatsis only in the comparison of the extreme conditions: those with scarce infiltration versus the ones with large infiltration. Inflammatory or plasmacellular infiltration may represent both a defense mechanism against cancer and an aspecific or allergic reaction. The eosinophilic infiltration shows no value in the prevention of nodal involvement.

Using analytical morphometry to distinguish severe dysplasia and large bowel carcinoma.

The aim of the present paper is to find analytical parameters to distinguish severe dysplasia from cancer. A population of 150 nuclei was selected randomly from: 5 cases of large bowel carcinoma, 5 cases of adenomatous polyps with severe dysplasia--according to Kozuka's criteria--(without any reference to the architecture: tubular, tubulo-villous and villous) and 5 cases of normal mucosa as control. The files of the coordinates of the nuclear contours were submitted to the S.A.M. (Shape Analytical Morphometry) work-station, which produces quantitative parameters (area, perimeter, maximum diameter and Roundness Factor) as well as analytical shape-descriptors. The latter were extracted by the S.A.E. (Shape Asymmetry Evaluator) procedure, which evaluates the symmetry of each contour studied, and by Fourier harmonic analysis which breaks up each curve into a defined set of harmonics which are then used to perform statistical tests. In the comparison between normal and severe dysplastic nuclei, normal and carcinomatous nuclei and severe dysplastic and carcinomatous nuclei univariate statistical evaluation (Student t test) proved to be highly significant for the most of the analytical parameters.