Comparison of glatiramer acetate (Copaxone) and interferon beta-1b (Betaferon) in multiple sclerosis patients: an open-label 2-year follow-up.

OBJECTIVE: To compare the clinical efficacy, as expressed by relapse rate and disability accumulation, and safety profile of glatiramer acetate (Copaxone; COP-1) and Interferon beta-1b (Betaferon; IFN beta - 1b) administered to multiple sclerosis patients during a 2-year follow-up on an open-label parallel design, as compared to their clinical condition in the 2-year period prior to treatment. BACKGROUND: Copaxone and IFN beta - 1b have been recently introduced for the treatment of relapsing forms of MS. Both medications have been proven to have a relatively safe profile and are used extensively world-wide. METHODS: 58 consecutive patients with relapsing forms of MS were enrolled from the MS out-patient clinic, during three months. After being informed in detail of the two approved treatment options existing at the time in Israel, the patients chose by themselves to receive either: (a) Copaxone 20 mg subcutaneously (sc) daily (Copaxone dly, 20 patients), or (b) Copaxone 20 mg sc alternate-day (Copaxone alt, 18 patients) or (c) IFN beta-1b 8 MIU sc in alternate day (20 patients). Mean relapse rate/year and mean EDSS/year were calculated for each group of patients during the 2 years prior to the onset of treatment, and during the year prior to the onset of treatment. Statistical significance was observed in the relapse rate in the year prior to the onset of treatment between the IFN beta -1b group and the two Copaxone groups (p = 0.05). This statistical difference has no effect on the overall data of the 2 years prior to starting the treatment and on the results. No statistical significance was observed in the total number of relapses, and on the 2-year relapse rate, prior to the onset of treatment. Mean relapse rate/year and mean EDSS/year were calculated for each group during the first and second year of treatment. Wilcoxon analysis for clinical data and chi-square for adverse events were applied. RESULTS: The three groups were statistically comparable concerning mean relapse/year in the 2 years before the trial started and no statistical significance was observed among the three groups. A statistically significant reduction in the mean relapse rate in the 2 years after onset of treatment was observed in the three group of patients: Copaxone daily (dly) 1.1 +/- 0.6 (p = 0.0001); Copaxone alternate (alt) 0.9 +/- 0.6 (p = 0.0004) and IFN beta -1b 1.2 +/- 0.7 (p = 0.0001). Disability as expressed by EDSS score prior to the onset of treatment and after 2 years of treatment showed deterioration in the three groups although more significant in the Copaxone groups: Copaxone dly 3.3 +/- 1.4 to 3.8 +/- 1.6 (p = 0.007); Copaxone alt 2.4 +/- 1.1 to 2.8 +/- 1.3 (p=0.04); IFN beta - 1b 3.1 +/- 1.3 to 3.3 +/- 2.0 (N.S.). The most common adverse events reported were: (1) flu-like symptoms 7 pts (35%) in the IFN beta -1b group; 10 pts (26%) of the two Copaxone groups; (2) increased spasticity of lower limbs 3 pts (15%), only in the IFN beta -1b group; (3) site injection reaction (SIR): 16 SIR (80%) in the IFN beta -1b group; 12 SIR (67%) in the Copaxone alt group; 14 SIR (70%) in the Copaxone dly group; and (4) systemic reaction 3 pts (15%) in the IFN beta -1b group; 4 pts (22%) in the Copaxone alt group; 6 pts (30%) in the Copaxone dly group. Premature termination occurred in five patients treated with Copaxone (3 in the alternate group and 2 in the daily group). CONCLUSION: The present study, despite the limitations of an open-label study, shows that Copaxone dly, Copaxone alt and IFN beta -1b treatment seem to be equally effective for the control of exacerbations in MS. The adverse event profile, as reported by the patients, was also similar. However, the adverse events profile registered indicated that Copaxone is somewhat less detrimental, whereas disability as measured by EDSS accumulation showed that the interferon beta - 1b patients demonstrated a slower progression of the disability.

Identification in Israel of 2 Jewish Creutzfeld-Jakob disease patients with a 178 mutation at their PrP gene.

Among the dozen known mutations in the PrP gene which segregate with the inherited prion diseases, only 2 mutations have been described in Israel so far: the codon 200 mutation in Creutzfeldt-Jakob disease (CJD) affected Libyan Jews, and the codon 102 mutation in 1 Jewish Gerstmann-Straussler-Scheinker (GSS) affected pedigree of German origin. We report here 2 unrelated CJD178 cases affected by a unique phenotype: aphemia, apraxia, uncontrolled laugh and no ataxia. As opposed to other CJD178 patients, in these patients, the signal transduction protein 14-3-3, recently suggested as a CJD marker, was detected in the cerebrospinal fluid samples by immunostaining. The D178N mutation, known to be linked to 2 different phenotypes: Fatal Familial Insomnia (FFI) and CJD, was not described so far among Jews. The phenotype reported here, although it shares a common Va1129/Asn178 haplotype with the previously described CJD178, may point to a different clinical subtype of CJD178.

Pure red cell aplasia responsive to interferon-alpha in a patient with hepatitis C virus infection.

A 51-year-old man presented with severe anemia, mild splenomegaly and elevated serum aspartate aminotransferase and serum alanine aminotransferase levels. The bone marrow findings were consistent with pure red cell aplasia (PRCA) with a 'maturation arrest' at the level of pronormoblast. The patient has been transfusion-dependent for 8 months. Following diagnosis of chronic active hepatitis due to hepatitis C virus (HCV), therapy with interferon-alpha was initiated. Two weeks later, the hemoglobin level stabilized, and he has not required any transfusion ever since. In spite of ongoing HCV viremia, cessation of interferon therapy, and deterioration of the liver function tests, the patient, followed for 2 years, maintains a high-normal hemoglobin level. To the best of our knowledge, this is the first report of prolonged PRCA corrected by interferon-alpha therapy, with or without an ongoing HCV infection. We speculate that the 'maturation arrest' of the erythroid lineage seen in the bone marrow was the result of an immune mechanism, possibly induced by the HCV, and that the elimination of this mechanism, rather than the elimination of the HCV, provided the opportunity for regeneration of erythropoiesis.

The enigma of parkinsonism in chronic borderline mercury intoxication, resolved by challenge with penicillamine.

A 47 year old female dentist suffered from hemiparkinsonism which had started eighteen months earlier and was manifested mainly by resting tremor and cogwheel rigidity. A baseline quantitative urinary mercury excretion was 46 micrograms/day. The patient was treated with chelating agent d-penicillamine for a week. Chelation therapy resulted in clinical improvement of parkinsonism and in dynamic changes in daily urinary mercury excretion with a prompt increase to 79 micrograms/day, a subsequent decline followed by increase in the mercury urinary excretion. After a week chelation therapy was stopped. During a follow-up period of five years, the neurological status remained unchanged after the initial penicillamine-induced improvement. This case may be evidence, therefore, of a rare clinical variant of elemental mercury intoxication associated with parkinsonism, in the absence of most classical neuropsychiatric signs of chronic mercurialism.

L'homme qui rit: inappropriate laughter and release phenomena of the frontal subdominant lobe.

Witzelsucht and moria are time-honored neurobehavioral terms. Witzelsucht is a tendency to tell inappropriate jokes, and moria is euphoric behavior. Focal right-orbitofrontal parenchymal lesion is often the anatomical substrate for these behavioral attitudes. This case report presents a patient with a longstanding witzelsucht-moria behavior. Single photon emission computerized tomography (SPECT) showed hypoperfused right-frontoparietal area in the absence of structural damage.

The value of exploratory laparotomy in patients with endometrial carcinoma according to the new International Federation of Gynecology and Obstetrics staging.

OBJECTIVE: We conducted a retrospective review of 169 consecutive patients diagnosed with endometrial carcinoma to evaluate the advantage of exploratory laparotomy according to the new International Federation of Gynecology and Obstetrics (FIGO) classification as compared with clinical staging. METHODS: All 169 patients were admitted to the Department of Gynecologic Oncology from August 1980 through June 1988 and underwent exploratory laparotomy, which included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings. We performed complete lymph node dissection of the pelvic and the para-aortic areas on 87 patients with clinical stages I and II. Eighteen more patients were upgraded to stage III or IV during exploratory laparotomy with lymph node biopsy. Forty-nine patients did not have lymph node dissection because of age and medical contraindications. In 15 patients with clinical stage III or IV, lymph node dissection was performed as part of debulking surgery. Clinical staging showed 135 patients (80%) with stage I, 19 (11%) with stage II, three (2%) with stage III, and 12 (7%) with stage IV carcinoma. RESULTS: Surgical restaging according to the new FIGO classification resulted in 117 patients (69%) with stage I, seven (4%) with stage II, 23 (14%) with stage III, and 22 (13%) with stage IV carcinoma. Thirty patients (19%) of 154 with clinical stage I or II had extrauterine spread. Thirty-three of 169 patients (19.5%) had their clinical staging upgraded and six (3.5%) were downgraded. The 5-year actuarial survival rates for clinical stages I, II, and IV were 83, 64, and 8%, respectively. The actuarial survival rates for surgical stages I, II, III, and IV were 89, 100, 58, and 24%, respectively. Cases surgically staged as I with high-risk variables (eg, poor differentiation, unfavorable histologic types, and deep myometrial invasion) or stage II received 5000 cGy to the whole pelvis using a box technique. Patients with surgical stage III or IV received adjuvant intravenous chemotherapy (eg, doxorubicin, hydrochloride, Cytoxan, and cisplatin) consecutively for ten to 12 courses. Megestrol acetate was added for 2 years. CONCLUSIONS: Surgical staging after exploratory laparotomy defined the true extent of disease and identified 20% of the cases that may escape effective treatment.

Tumor debulking followed by immediate combination chemotherapy in advanced ovarian carcinoma. Phase II.

Fifty-one consecutive, previously untreated patients with FIGO stage III or IV epithelial ovarian carcinoma were enrolled in a prospective study over a period of 7 years (1981-1988). Significant improvement has been noted in patients with advanced ovarian cancer following the administration of modified PAC 1 (adriamycin, cytoxan and cyclophosphamide) immediately following primary debulking surgery (within 24 hours) and repeated for 11 monthly cycles. A second look operation was found as an important prognostic indicator. Thirty-one patients (all Stage III) completed the chemotherapy course and were eligible for second look operation. Of these, 21 patients (68%) showed negative second look. Of the patients with negative second look, 17 of 21 (81%) are alive with a mean survival of 61 months (range 19-103 months) after diagnosis. Among those with positive second look only 3 of 10 are alive with a mean of 41 months after diagnosis. The remaining 20 patients (13 stage III and 7 stage IV) did not undergo second look laparotomy. Only 2 of these 20 patients are alive with a mean of 35 months after diagnosis. Other factors of significant importance were: age and completion of chemotherapy course. Patients appeared to benefit from the combined regimen of optimal debulking surgery, completion of 12 courses of chemotherapy with the first course administered immediately after surgery and second look operation. Tumor type or histologic grade did not seem to influence results. The early use of chemotherapy was well tolerated and toxicity was minimal and acceptable.

Impulsive artistic creativity as a presentation of transient cognitive alterations.

A 27-year-old right-handed male mosaic artisan who had not shown any interest in drawing or artistic activity was admitted to the Department of Neurology for attacks of bizarre behavior and convulsive disorder. The patient reported feeling "waves" engulfing him during the attacks, leaving him floating helplessly. During some attacks, the patient impulsively initiated drawing activity. Interictal sleep-deprivation EEG showed a left frontotemporal focus of paroxysmal discharge. Brain tomography with SPECT showed low 99Tc-HMPAO uptake in the left frontoparietal region. Psychodiagnostic tests gave evidence of dysfunction of the left frontal region, with preference of the right hemisphere. It is suggested that the attacks of altered cognitive state were, in this case, provoked by spreading depression of the left hemisphere, while the integrative functions of the right hemisphere remained intact. Thus, the impulsive artistic creativity during the attacks may represent a "release phenomenon" of the complex visuospatial skills of the right (subdominant) hemisphere. This symptomatology of transient cognitive alterations is unique and, to the best of our knowledge, has not been previously reported.

Plasma lipid-associated sialic acid and serum CA 125 as indicators of disease status with advanced ovarian cancer.

Levels of plasma lipid-associated sialic acid and serum cancer antigen 125 (CA 125) were measured in 49 consecutive patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stages III or IV) and in 43 women with benign gynecologic diseases who served as controls. Levels were evaluated in 22 previously untreated patients before initial debulking surgery, in 11 with negative second-look operation, and in 16 with persistent or progressive disease confirmed by second-look operation or reexploration. Plasma lipid-associated sialic acid values had a sensitivity of 100% in previously untreated patients, a specificity of 73% in those with negative second-look, and a sensitivity of 87% in those with positive second-look, or persistent disease. CA 125 values were 77, 100, and 75%, respectively. By combining both markers, there were no false-negative results in previously untreated patients or false-positive results in those who were disease-free. Only one of 16 patients with persistent disease had false-negative results for both markers and progressive disease on reexploration. The predictive values of a positive assay with plasma lipid-associated sialic acid, CA 125, and both markers combined were 92.3, 100, and 100%, respectively. The predictive values of a negative assay were 80, 55, and 88.9%, respectively. The combined use of plasma lipid-associated sialic acid and CA 125 enhanced the individual reliabilities of these tests in patients with advanced ovarian carcinoma.

Stage IV endometrial carcinoma in a 25-year-old woman: a case report and review of the literature.

Presented is a case of endometrial adenocarcinoma FIGO stage IV grade III in a 25-year-old woman with no evidence of any associated disease or known risk factors. To the best of the authors' knowledge this association has not been reported previously.

The feasibility of early administration of combination chemotherapy following cytoreductive surgery and second-look operation in patients with stage III ovarian carcinoma: a pilot study.

The purpose of this study is to evaluate the feasibility of early use of modified PAC-1 chemotherapy following debulking surgery and its efficacy by assessing disease status during a second-look operation. Twenty-six consecutive previously untreated patients with stage III ovarian carcinoma were evaluated in a prospective study over the 5-year period March 1981 to August 1986. Initial exploratory laparotomy was performed for staging and maximum cytoreduction. Within 24 hr postoperative modified PAC-1 (M-PAC-1) combination chemotherapy was administered and then repeated every 4 weeks for 11 months which was then followed by second-look operation. Patients were analyzed according to the following pretreatment characteristics: age, FIGO stage, histologic tumor type, extent of initial surgery, size of residual tumor, and findings during second-look. Nineteen patients were evaluable. No evidence of either microscopic or macroscopic disease was noted in 15 patients (79%), whereas the remaining 4 (21%) exhibited persistent disease. Of the remaining 7 patients not undergoing SLO, 4 completed 12 courses of chemotherapy but did not undergo surgery for medical reason (n = 2) or patient refusal (n = 2). Two more patients refused chemotherapy after 9 courses and the seventh patient expired with persistent disease after 8 courses. The early use of combination chemotherapy was well tolerated. Neurological, hematological, and renal toxicity was never severe enough to cause discontinuation of therapy.

Lipid associated sialic acid in plasma in patients with advanced carcinoma of the ovaries.

Plasma lipid associated sialic acid (LASA-P) was evaluated in relation to disease status and disease progression in a total of 52 consecutive patients with advanced carcinoma of the ovaries (FIGO stage III and IV). Forty-three individuals with benign gynecologic diseases served as controls. There were three groups. Group 1 included 23 untreated patients who had LASA-P values above normal before debulking operations. Group 2 consisted of 12 patients who completed 12 courses of chemotherapy after debulking operations and presented with negative findings at second look operation (SLO). LASA-P levels were measured in these patients prior to SLO. Eight of 12 patients had normal LASA-P values for a specificity rate of 67 per cent. Four patients had elevated values with no clinical evidence of disease. Group 3 had 17 patients who failed to respond to cytotoxic chemotherapy after initial debulking procedures. All patients in this group had persistent or recurrent disease that was documented at re-exploration or at SLO. Elevated LASA-P levels were noted in 14 of 17 patients for a sensitivity rate of 82 per cent. Rising LASA-P values in serial samples were the only signs of disease recurrence in three of five patients who completed 12 courses of chemotherapy and in whom SLO showed surgical evidence of disease. The predictive value for positive and negative results for all patients were 92.2 and 72.7 per cent, respectively. In spite of the relatively low sensitivity and specificity rates in groups 2 and 3, LASA-P can be used successfully as a valuable adjunct to monitor the course of the disease during treatment in patients with advanced carcinoma of the ovaries.

Malignant cystic meningioma with spike and wave EEG pattern.

A 23 year old woman suffering from grand mal epilepsy showed generalized spike and wave activity on her EEG. The CT showed a cystic tumor in the cortex and the white tissue of the right parietal region. On operation the tumor was diagnosed as malignant infiltrating cystic meningioma. After removal of the tumor the spike and wave pattern disappeared. Cortical localized tumors are rarely associated with a generalized spike and wave pattern.

Selective regional effect of various neuroactive drugs on bromocriptine concentration in the brain of rats.

Bromocriptine (2-Br-alpha-ergocryptine), a partial ergoline derivative, is a dopamine agonist which has been used successfully in the treatment of hyperprolactinemia, acromegaly and Parkinson's disease. The main targets for the action of the drug are the hypothalamic, hypophyseal pathway and the striatum. These regions contain different populations of neurons which interact with each other in a complex way. In order to check the mechanism of these interactions in rats, we administered different neuroactive drugs together with bromocriptine. After a single intraperitoneal injection, bromocriptine concentration in the striatum was 13.1 +/- 2.9 ng/mg protein, and in the hypothalamus 13.9 +/- 0.8 ng/mg protein. The largest increase in the bromocriptine content in the striatum was found after the concomitant administration of naloxone, an opiate receptor blocker (21.2 +/- 2.5 ng/mg protein). The largest increase of the bromocriptine content in the hypothalamus was found after the concomitant injection of methysergide, a serotonin receptor blocker (27.8 +/- 2.6 ng/mg protein). Amantadine, diazepam and haloperidol caused the largest decrease in the two regions. The mechanism of interaction and therapeutic implication of these findings are discussed.

Thymectomy and chronic relapsing experimental allergic encephalomyelitis in guinea pigs.

Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in young Dunkin Hartley guinea pigs by a single sensitization with guinea pig spinal cord homogenate. The effect of either newborn thymectomy or young adult thymectomy on the clinical course of chronic and relapsing EAE was studied and evaluated statistically by Student's t test. All the animals that underwent thymectomy showed a significant delay in the onset of the disease compared with control groups. In addition, in the young adult guinea pigs in which thymectomy was done, the incidence of clinical disease was decreased. No substantial differences, however, were observed in the severity of the disease and number of remissions or relapses between guinea pigs in which thymectomy was done and in which clinical symptoms developed and controls.

Effect of various neuroactive drugs on bromocriptine concentration in the striatum of rats.

Parkinsonian patients are usually given several drugs concomitantly with bromocriptine, with variable results. The possibility of interference of these drugs with the availability of bromocriptine in the brain was investigated by measuring bromocriptine concentrations in the striatum in rats. After a single injection, bromocriptine concentration in the striatum was 13.1 +/- 2.9 ng/mg protein. Naloxone, an opiate receptor blocker, was found to produce the largest increase in bromocriptine content (21.7 +/- 2.5 ng/mg protein). Amantadine, diazepam and haloperidol produced the largest decreases (3.2 +/- 0.9, 3.3 +/- 0.8 and 4.4 +/- 1.2 ng/mg protein, respectively). Rats given L-dopa or benzodiazepine also showed slightly lower levels of bromocriptine.

Convulsive attacks due to antidepressant drug overdoses: case reports and discussion.

Antidepressant drug overdoses have been reported to induce seizures, but the etiology of this phenomenon is still unclear. Recently we treated three patients who suffered from epileptic seizures after acute overdoses of three antidepressant drugs: (a) Dibenzepin HCl (Noveril), (b) Maprotiline HCl (Ludiomil), and (c) Clorimipramine (Anafranil). After a review of the pertinent literature, the possible role of antidepressant drugs in the genesis of epileptic seizures is discussed.