Methodology
Subjects and Methods
I- Site of the Study :
The study was performed in the Institute of Psychiatry, Ain Shams University Hospitals in the period from, March, 1998 to the end of March 2000 (including the time of the pilot study).
II- Subjects :
1-Patient Group :
��������� A selected sample formed of 20 patients and 10 controls were selected from the inpatients admitted to the institute of psychiatry, Neuropsychiatry department, Ain shams University hospitals.
a- Inclusion Criteria
1- The selected patients belonged to an adult comparable group of the same age , sex , social background and educational status.
2- Patients were medically free (other than psychiatric morbidity).
3- Patients were free from any Neurological disorder .
4- The presented sample will be chosen to fulfill the diagnostic� criteria of schizophrenia according to the International Classification of Disease (tenth 10th edition) diagnostic guidelines for research .
5- The selected sample of patients should have been drug naive i.e. First episode of schizophrenia or a patients in relapse with discontinuation of drug therapy and electroconvulsive therapy for at least six months .
b- Exclusion Criteria :
1-Patients who received neuroleptic medication or Electroconvulsive therapy for past six months .
2-Patients showing comorbidity of other psychiatric disorders.
3-History of neurological diseases as cerebrovascular disorders, degenerative brain diseases, inflammatory brain disease and neoplastic brain disease.
4-Patients with evident Family history of collagen disorders
5-Patients with evident medical disorder
6-History of significant medical disease that may affect CBF and SPECT findings as hypertension, diabetes mellitus, atherosclerosis, ischemic heart disease, chronic respiratory disease, malignancies and blood diseases.
7-Pregnant and lactating females because of the hazards of radioactive substance on the embryo or the baby.
8-Left handed subjects as CBF is related to handedness of the subject.
9-Heavy smokers were excluded as nicotine may affect CBF.
10-Patients who are receiving any medications with possible effects on CBF as diuretics.
2-Control Group
The control group consisted of 12 individuals with no apparent physical or psychiatric morbidity. They were matched for age, sex and other demographic variables as far as possible with the patient group. The control group was selected from the relatives of patients admitted to internal medicine department Ain Shams University Hospitals.
Exclusion criteria for control Group :
1.History of psychiatric disorder.
2.History of neurological disorder.
3.History of significant medical disease.
4. Age above 50 or below 20 years old.
5. Lactating or pregnant females.
6. Left handed subjects.
7.Heavy smokers.
8.Patients who are receiving any medications with possible effects on CBF as diuretics.
9.Patients who are receiving psychotropic medications.
c) Selection of Cases :
The cases were selected from Inpatients admitted to the Institute of Psychiatry, Ain Shams University Hospitals.
i- The Institute of Psychiatry
It is located in eastern Cairo, and serves a catchment area of about the third of Greater Cairo (approximately of 2-3million adults). It serves both urban and rural areas ,including areas around greater Cairo as well. The Institute of Psychiatry has 3 outpatient clinics daily for 5 days per week. On average 25-35 patients attend each of those 3 clinics daily. The Institute is subdivided into paid and non-paid sections. About 750 Cases are admitted to institute yearly of which approximately (50%) are diagnosed as Schizophrenia.
ii- Selection of Cases
The cases were selected from patients admitted to inpatient department on Sunday, Wednesday of each week. The size of the sample was originally 234 patients but only 20 patients fulfilling the inclusion criteria. The difference was large because there were a lot of medicated patients, smokers and patients refusing SPECT for hazards of radiation.
Method of the study
I- Procedures:
A) Pilot Study
The study proper was preceded by a pilot study in the period from the beginning of March 1998 to the end of January 1999.
Objectives
-To determine the size and method of selection of the sample.
-To assess the reliability of clinical diagnoses using different Tools used .
Results
During the period of pilot study it was found that the number of patients who fulfilled the inclusion criteria and attended out patient clinics monthly was between 4-6 patients. The total number of patients seen through the period of pilot study was 119 patients and only 25 of them were admitted . All the patients found during this period were also seen by one of the senior consultant to recheck the reliability of the diagnoses. (K=0.94).
B- The study proper
A- The study proper was performed in the Institute of Psychiatry, Ain Shams University Hospitals in the period from, January 13th , 1999� to the end of 30th April 2000 .
B-The sample for the study was chosen according to International Classification of Disease (tenth edition) diagnostic guidelines for research .(ICD-10) :
- ICD-10 symptom checklist
- Further assessment by psychiatric sheet of the Institute of Psychiatry.
C- Oral informed consent:
Patients and their admitting family members have been given full information about the protocol, nature and aim of the study and that they had the opportunity to discuss the issues relevant to the provision of their consent. Also patients and their admitting family members are informed by the possible benefits and risks that may be associated with the procedures of the study and that they had the possibility to withdraw themselves from the study at any time.
The chosen sample� were classified� according to the Anderson Scales of Positive and Negative symptoms to fulfill the criteria of three syndrome defined by Liddle et al (1992) . After diagnosis all patients and control subjects were subjected to the following:
1- Full psychiatric history and examination (copy of sheet model is present in the appendix).
2-Full general examination just before the SPECT.
3-Full cardiological and chest examination.
4-Full neurological examination including signs of autonomic hyperactivity just before the SPECT.
5-Assessment of all patients by routine laboratory Tests to exclude and patient with a medical illness that can alter the regional cerebral blood flow to the brain� study. These Tests included CBC , ESR , Fasting Blood sugar, Liver and renal Functions .
6- Assessment by PANSS� on the day of� performing the SPECT study.
99-Tc99 HMPAO brain SPECT :
7- The regional cerebral blood flow with single-photon emission Tomography using technetium-99m hexamethylpropylene amine oxime (Tc-99m-HMPAO-SPECT) method as following :
- Each patient took a look on the apparatus, information about the procedure and one hour rest before the SPECT procedure.
- Each subject was prepared by fixing an I.V. line .
- 99mTc UMPAO was prepared under aseptic technique and a calculated dose according to the patient's age ,weight was administered through the I.V. cannula followed by saline wash (about 5 ml).
- SPECT imaging started 20-30 minutes after radiopharmaceutical administration.
- Sophy gamma camera, DSX rectangular, was used with a computer system controlling the acquisition parameters and performing data processing functions.
- Parallel hole low energy super high resolution collimator was used (limit of resolution 5.5 mm).
- The patient was lying in supine position with his or her head fixed using especially designed pillow to immobilize the head while imaging.
- Data were acquired using step and shot technique. The image matrix format of 64x64w was selected. The camera head rotated through 360 around the patient's head with 64 stops or projections (angular interval of 5.6). An elliptical orbit was followed to minimize the distance between the patient's head and the collimator surface. About 1.5-2 million counts were acquired per study. Time per projection ranged from 20 to 30 second which means total imaging time of 22 to 32 minutes.
- The acquired data were displayed in cine mode before processing manipulation to confirm steady head in position throughout the imaging time.
- Transaxial slices of the brain were reconstructed from the posterior fossa up to the vertex of the brain using standard filtered back projection technique. The Hamming-Hann filter was used. Nor attenuation correction was made. The brain- reconstructed volume was reoriented so as to make the transverse plane parallel to the orbito-meatal line.
- Three transaxial slices (I pixel thick) were selected for semiquantitative analysis. The bottom slice corresponded to the cerebellum. The middle slice was at the level of the basal and temporal regions. The upper slice was taken at a higher level to represent the superior frontal and parietal cortex. Regions of interest (ROls:20x20 pixels) were symmetrically drawn on the three selected slices.
- Three ROls were selected on each cerebellar hemisphere. Three pairs of ROls were placed on the inferior frontal regions, two pairs on the basal ganglia, three pairs on the temporal regions and three pairs on the occipital regions.
- On the upper slice, three pairs of ROls were also drawn on the superior frontal and parietal regions.
- Counts of each anatomical region were calculated from the average of the counts of all 20x20x Ivoxels in the corresponding regions.
- The cerebellar hemisphere recorded the highest apparent perfusion in all the studied subjects (white color). So, the cerebellar activity was taken as a point of reference for each study to calculate the perfusion in the different cortical and subcortical regions. The calculation assumed a score of 1 for the cerebellar activity in each study. Regional HMPAO uptakes (i.e. RCBF) were calculated as ratios of average cortical or basal ganglia counts to average cerebellar activation.
8- Patients received antipsychotic treatment of equivalent dose to 800-1200 mg chlorpromazine using Risperdone , a new antipsychotic whose action is mediated through a combination of Dopamine type 2 (D2) and Serotonin type 2 (5HT2) antagonism. A daily dose of 4-6 mg was prescribed to the patients .
9- Follow-up was done once weekly using Clinical Global impression scale for Severity and for improvement.
10- The Tc-99m-HMPAO-SPECT and PANSS was repeated at least 6 weeks or more after the initiation of therapy� .
Control :
Sample were selected according to General health questionnaire .
All personal were subjected to measurement of regional cerebral blood flow with single-photon emission Tomography using technetium-99m hexamethylpropylene amine oxime (Tc-99m-HMPAO-SPECT) .
Tools
-ICD-10 checklist :
The ICD-10 Symptom Checklist for Mental Disorders is a semi-structured instrument intended for clinicians' assessment of the psychiatric symptoms and syndromes in the �FO-F6 categories of the International Classification of Diseases, Tenth Revision. Theinstrument consists of. (i) Face Sheet, (ii) Screener and (iii) Modules. The following modules are included in the �checklist.
Each of the modules consists of a symptom list and lists of states that, according to the ICD- 10 criteria, should he excluded or could be associated with the syndrome. These lists are accompanied by instructions that may help the user in considering older possible syndromes and hence the use of other modules in the checklist( .
- Positive and Negative syndrome scale manual :
The Positive and Negative Syndrome Scale (PANSS) was developed and standardized for logical and dimensional assessment of schizophrenic phenomena. The 30-item, seven-point rating instrument was conceived as a carefully defused and operationalzed method that evaluates positive, negative, and other symptom dimensions on the basis of a formal semi-structured clinical interview and other informational sources. The available PANSS instrument includes 30 items which are scored for:
� Positive Scale
�Negative Scale
�Composite� (Positive minus Negative)
�General Psychopathology Scale .
Theoretically, the PANSSserves the need for focused evaluation of positive and negative dimensions of schizophrenic disorder. Thus, of the 30 item, seven are grouped to form a Positive Scale, measuring symptoms that are superadded to a normal mental status, and another seven items constitute a Negative Scale, assessing features absent from a normal mental status. Based on the differential been these scales, a. Finally, the general psychopathology Scale, gauges the overall severity of schizophrenic disorder by summation of the remaining� 16 items.
-Clinical Global Impression:
The Clinical Global Impressions (CGI) Scale (Guy 1976) is a standardized assessment tool. Its goal is to allow the clinician to rate the severity of illness, change over time, and efficacy of medication, taking into account clinical condition of the patient and the severity of side effects. The CGI Scale is widely used in clinical psychopharmacology trials as an outcome measure.
- General Health Questionnaire (GHQ)
The GHQ is a self administered questionnaire for the detection of mental disorders and has been used successfully in community settings and non psychiatric clinical settings in many countries (Goldberg and Williann, 1988) .
-Single-photon emission Tomography (SPECT):
which was previously discussed in details in chapter 2 and� in step 7 of the procedures .
Statistical Analysis
All the data were recorded on investigative report form. This data transferred to IBM card. Using personal computer with statistical program (Statistical Package For Social Sciences (SPSS) version 7.5 to obtain:
1 -Descriptive statistics
a) Mean ( x- )
b) Standard deviation ( + SD )
c) Range (Min-max)
2-Analytical statistics
A) Student's t test:
A statistic used to test for a significant of an independent variable in experiments where there are only two levels of this variable (to compare between 2 independent means).
B) Paired-Samples T Test:
The Paired-Samples T Test procedure compares the means of two variables for a single group. It computes the differences between values of the two variables for each case and tests whether the average differs from 0.For each pair of variables: correlation, average difference in means, T-test, and confidence interval for mean difference, Standard deviation and standard error of the mean difference.
C) BavariateCorrelations :
The Bivariate Correlations procedure computes Pearson's correlation coefficient, Spearman's rho and Kendall's tau-b with their significance levels. Correlations measure how variables or rank orders are related. For each pair of variables: Pearson's correlation coefficient, Spearman's rho, Kendall's tau-b, cross-product of deviations, covariance.
C) Analysis of variance (ANOVA):
This is a set of statistical procedures designed to test for a significant of an independent variable in experiments where there are two or more levels of this variable.
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