VALIDATION OF THE BRIEF INTERNATIONAL COGNITIVE ASSESSMENT FOR MULTIPLE SCLEROSIS (BICAMS) IN A LARGE COHORT OF RELAPSING-REMITTING MS PATIENTS.

Cognitive impairment is one of the most frequently reported symptoms in persons with multiple sclerosis (MS). The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been recommended as a standardized international screening and monitoring tool for brief cognitive assessment. The aim of our study was to assess the reliability and validity of the Serbian version of the BICAMS. A total of 500 relapsing-remitting MS (RRMS) patients and 69 age-, gender- and education-matched healthy control (HC) subjects were examined. All participants performed the BICAMS test battery, which includes the oral version of the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test second edition (CVLT-II), and Brief Visuospatial Memory Test Revised (BVMTR). A randomly selected subset of patients were retested one to three weeks after baseline. Statistically significant differences between patients and HCs were evident on the SDMT and BVMTR (p<0.001). HCs had higher CVLT-II scores but this difference did not reach statistical significance (p=0.063). Cognitive impairment, defined as an abnormal test score on ≥1 subtest, was found in 62.9% of MS patients. There were statistically significant correlations between BICAMS scores and age, education, EDSS and disease duration in patient sample. Test-retest reliability was confirmed with Pearson correlation coefficient of 0.70 in all measures. This study supported the reliability and validity of the Serbian BICAMS, although the CVLT-II version tested here lacked sensitivity to detect MS compared to healthy volunteers.

Superoxide dismutase (SOD), advanced oxidation protein products (AOPP), and disease-modifying treatment are related to better relapse recovery after corticosteroid treatment in multiple sclerosis.

OBJECTIVES: The aim of our study was to analyze oxidative stress (OS) markers in multiple sclerosis (MS) patients during relapse and remission and to evaluate the effects of corticosteroid relapse treatment on oxidative status, and also to determine possible relationship between OS markers and relapse disability recovery after corticosteroid treatment. METHODS: Our study included 118 MS patients, (59 relapse/59 remission) 70 females and 48 males, mean age 40.2 ± 9.4 years, and 88 matched healthy controls. Undergoing disease-modifying therapy (DMT) was present in 30.5% of relapse and 88% of remission MS patients. We analyzed in plasma/serum the following: pro-oxidative-antioxidative balance (PAB), nitrates and nitrites (NO3 + NO2), malondialdehyde (MDA), advanced oxidation protein products (AOPP) superoxide dismutase (SOD), catalase (CAT), uric acid, bilirubin, albumin, and transferrin in all patients and additionally after corticosteroid relapse treatment. Neurological disability was measured using the Extended Disability Status Scale (EDSS). RESULTS: Better clinical recovery after relapse treatment was associated with increased baseline SOD, decreased AOPP, and ongoing DMT (all p < 0.05). There was no difference between OS markers in relapse and remission. MS patients had higher MDA, NO3 + NO2, PAB, SOD, CAT, lower AOPP, uric acid, albumin, bilirubin, and transferrin compared to controls (all p < 0.05). Corticosteroids caused significant decrease of all OS markers (all p < 0.05). CONCLUSION: Increased baseline antioxidative activity of SOD and decreased baseline levels of pro-oxidant AOPP along with ongoing DMT were related to better clinical recovery after corticosteroid relapse treatment. Increase of pro-oxidants and antioxidant enzyme activity in relapse and remission confirms ongoing oxidative injury irrelevant of MS clinical presentation.

Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement.

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

Autologous hematopoietic stem cell transplantation in combination with immunoablative protocol in secondary progressive multiple sclerosis--A 10-year follow-up of the first transplanted patient.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that affects young individuals and leads to severe disability. High dose immunoablation followed by autologous hemopoietic stem cell transplantation (AHSCT) has been considered in the last 15 years as potentialy effective therapeutic approach for aggressive MS. The most recent long-time follow-up results suggest that AHSCT is not only effective for highly-aggressive MS, but for relapsing-remitting MS as well, providing long-term remission, or maybe even cure. We presented a 10-year follow-up of the first MS patient being treated by immunoablation therapy and AHSCT. CASE REPORT: A 27-year-old male experienced the first symptoms--intermitent numbness and paresthesia of arms and legs of what was treated for two years by psychiatrist as anxiety disorder. After he developed severe paraparesis he was admitted to the Neurology Clinic and diagnosed with MS. Our patient developed aggressive MS with frequent relapses, rapid disability progression and transition to secondary progressive form 6 years after MS onset[the Expanded Disability Status Scale (EDSS) 7.0 Ambulation Index (AI) 7]. AHSCT was performed, cyclophosphamide was used for hemopoietic stem cell mobilization and the BEAM protocol was used as conditionig regimen. No major adverse events followed the AHSCT. Neurological impairment improved, EDSS 6.5, AI 6 and during a 10-year follow-up remained unchanged. Brain MRI follow-up showed the absence of gadolinium enhancing lesions and a mild progression of brain atrophy. CONCLUSION: The patient with rapidly evolving, aggressive, noninflammatory MS initialy improved and remained stable, without disability progression for 10 years, after AHSCT. This kind of treatment should be considered in aggressive MS, or in disease modifying treatment nonresponsive MS patients, since appropriately timed AHSCT treatment may not only prevent disability progression but reduce the achieved level of disability, as well.

Urgent carotid stenting before cardiac surgery in a young male patient with acute ischemic stroke caused by aortic and carotid dissection.

Introduction: Acute aortic dissection (AD) is the most common life-threatening disorder affecting the aorta. Neurological symptoms are present in 17-40% of cases. The management of these patients is controversial. Case report: We presented a 37-year-old man admitted for complaining of left-sided weak-ness. Symptoms appeared two hours before admission. The patient had no headache, neither thoracic pain. Neurological examination showed mild confusion, left-sided hemiplegia, National Institutes of Health Stroke Scale (NIHSS) score was 10. Ischemic stroke was suspected, brain multislice computed tomography (MSCT) and angiography were performed and right intrapetrous internal carotid artery dissection noted. Subsequent color Doppler ultrasound of the carotid arteries showed dissection of the right common carotid artery (CCA). The patient underwent thoracic and abdominal MSCT aortography which showed ascending aortic dissection from the aortic root, propagating in the brachiocephalic artery and the right CCA. Digital subtraction angiography was performed subsequently and two stents were successfully implanted in the brachiocephalic artery and the right CCA prior to cardiac surgery, only 6 hours after admission. The ascending aorta was reconstructed with graft interposition and the aortic valve re-suspended. The patient was hemodynamically stable and with no neurologic deficit after surgery. Unfortinately, at the operative day 6, mediastinitis developed and after intensive treatment the patients died 35 days after admission. Conclusion: In young patients with suspected stroke and oscillatory neurological impairment urgent MSCT angiography of the brain and neck and/or Doppler sonography of the carotid and vertebral artery are mandatory to exclude carotid and aortic dissection. The prompt diagnosis permits urgent carotid stenting and cardiosurgery. To the best of our knowledge, this is the first published case of immediate carotid stenting in acute ischemic stroke after the diagnosis of carotid and aortic dissection and prior to cardiac surgery

Gender-related differences in clinical presentation, electrocardiography signs, laboratory markers and outcome in patients with acute pulmonary embolism.

Background/Aim: Acute pulmonary embolism (PE) is a potentially life threating event, but there are scarce data about genderrelated differences in this condition. The aim of this study was to identify gender-specific differences in clinical presentation, the diagnosis and outcome between male and female patients with PE. Methods: We analysed the data of 144 consecutive patients with PE (50% women) and compared female and male patients regarding clinical presentation, electrocardiography (ECG) signs, basic laboratory markers and six-month outcome. All the patients confirmed PE by visualized thrombus on the multidetector computed tomography with pulmonary angiography (MDCTPA), ECG and echocardiographic examination at admission. Results: Compared to the men, the women were older and a larger proportion of them was in the third tertile of age (66.0% vs 34.0%, p = 0.008). In univariate analysis the men more often had hemoptysis [OR (95% CI) 3.75 (1.16-12.11)], chest pain [OR (95% CI) 3.31 (1.57-7.00)] febrile state [OR (95% CI) 2.41 (1.12-5.22)] and pneumonia at PE presentation [OR (95% CI) 3.40 (1.25-9.22)] and less likely had heart decompensation early in the course of the disease [OR (95%CI) 0.48 (0.24-0.97)]. In the multivariate analysis a significant difference in the rate of pneumonia and acute heart failure between genders disappeared due to strong influence of age. There was no significant difference in the occurrence of typical ECG signs for PE between the genders. Women had higher level of admission glycaemia [7.7 mmol/L (5.5-8.2 mmol/L) vs 6.9 mmol/L (6.3-9.6 mmol/L), p = 0.006] and total number of leukocytes [10.5 x 109/L (8.8-12.7 x 109/L vs 8.7 x 109/L (7.0-11.6 x 109/L)), p = 0.007]. There was a trend toward higher plasma level of brain natriuretic peptide in women compared to men 127.1 pg/mL (55.0-484.0 pg/mL), p = 0.092] vs [90.3 pg/mL (39.2-308.5 pg/mL). The main 6-month outcomes, death and major bleeding, had similar frequencies in both sexes. Conclusion: There are several important differences between men and women in the clinical presentation of PE and basic laboratory findings which can influence the diagnosis and treatment of PE.

Relapse of Takayasu arteritis as a cause of suicidal poisoning and subsequent major ischemic stroke successfully treated with thrombolytic therapy.

Introduction: Takayasu arteritis (TA) is a rare large vessel arteritis, affecting primarily aorta and its major branches. Its clinical manifestations can vary significantly - from asymptomatic to serious vascular events. Acute neurological complications are frequent at the onset of the disease and in relapses. Anxiety and depression are more frequent in TA patients than in general population as well as during relapses. Prevalence of transient ischemic attack or ischemic stroke in TA patients is approximately 10-20%. Case report: We presented a patient with TA that began with a depressive episode resulting in attempted suicide by bromazepame poisoning. This was subsequently followed by major ischemic stroke caused by thrombosis of the left middle cerebral artery (probably due to aortic arch embolism) successfully treated with intravenous thrombolysis. Conclusion: Intravenous thrombolysis appears to be safe and effective in patients with TA and stroke.

Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis.

BACKGROUND/AIM: Multiple sclerosis (MS) is an immune-mediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. METHODS: This study involved 60 consecutive MS patients--48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, non-immunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. RESULTS: The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). CONCLUSION: According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma.

Retinal periphlebitis in patients with multiple sclerosis.

BACKGROUND/AIM: Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss. Retinal periphlebitis (RP) is often present in MS patients with similar evolution and histopathological changes as MS lesions. The aim of this study was to analyze the presence of RP in MS patients during different clinical phases, and its connection with impairment of blood-brain barrier. METHODS: The study included 45 patients (26 females and 19 males) with MS. Their average age was 33.2 +/- 8.1 years. There were 28 patients with relapsing-remitting (RR) form, 7 with primary progresive (PP) and 10 with secondary progressive (SP) form of MS. There were 27 patients in the relapse and 18 patients in the remission phase. The average MS duration was 7.48 +/- 1.3 years. Ophthalmological, neurological and MRI examination were performed in all the patients, as well as cerebrospinal fluid sampling. Albumin ratio and IgG index were calculated in all the patients. RESULTS: There were 9 patients with RP, and 36 without it. MS duration was significantly longer in the RP group. RP was much more common in the progressive form and was not present in the remission phase of MS. Albumin ratio values were increased in the group with RP. IgG index and IgG synthesis according to Tourtellotte formula, were statistically higher in the group of patients with RP. The values of visual evoked potentials (VEP's) latency were significantly higher in the group of patients with RP. CONCLUSION: The presence of RP is a reliable indicator of MS activity and might be considered as a parameter for monitoring the disease activity and effects of the treatment.

Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention.

High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis - in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as 'high aggregation', and aggregation below the median as 'low aggregation'. Data below are medians and interquartile ranges. Patients with 'high platelet aggregability' had a significantly higher increase in both sCD40L (Delta-values: 0.78 (-0.19-3.18) vs. -0.65 (-2.10-0.00) ng/ml, P = 0.002) and sP-selectin (Delta-values: 8.0 (-2.00-16.00) vs. 4.50 (-13.00-0.50) ng/ml, P = 0.001) compared with patients with 'low platelet aggregability'. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.

Association of polymorphisms in CTLA-4, IL-1ra and IL-1beta genes with multiple sclerosis in Serbian population.

We have investigated separate as well as combined influence of IL-1beta TaqI, IL-1ra VNTR and CTLA-4 + 49 A/G polymorphisms on susceptibility, clinical course and progression of MS in 162 Serbian patients. We found significant independent relative risk for MS susceptibility in noncarriers of IL-1ra allele 2 (OR = 2.2, CI = 1.3-3.7, p = 0.003) and CTLA-4 + 49 AA genotype (OR = 2.0, CI = 1.2-3.5, p = 0.01) as well as their combined effect (OR = 4.4, CI = 2.0-9.7, p = 0.0003). Our result supports the significant and combined effect of IL-1ra VNTR and CTLA-4 polymorphisms on MS justifying the need for further haplotype analysis in different populations.

[Treatment of severe spacticity in multiple sclerosis by continuous intrathecal baclofen].

BACKGROUND: Successful treatment of severe spasticity represents an imperative of symptomatic therapy of multiple sclerosis (MS) due to a significant improvement of physical, psychic and social rehabilitation of MS patients, as well as a long-term cost savings for the additional treatments of conditions arising from uncontrolled severe spasticity. Continuous intrathecal administration of baclofen (ITB), using a subcutaneously implanted programmable infusion pump, is a minimally invasive, reversible method for the treatment of severe diffuse spasticity of the spinal origin. CASE REPORT: The first two cases in our country, treated by ITB due to severe spasticity caused by MS, were reported. Despite the local complications of surgical wound healing above the implanted components of the ITB-system in one patient, the optimal reduction of spasticity the with complete elimination of spastic pain was obtained in both patients. CONCLUSION: Our initial experiences confirmed ITB as a safe and effective therapeutical option for the treatment of intractable spasticity in patients with MS. Major prerequisites for this were adequate patient selection and good control of the basic disease. The use of the minimal invasive implantation technique and the experience in choosing of the adequate ITB-system components, could successfully prevent the occurrence of local complications related to the impaired healing of the ITB-system implantation site.

[Agenesis of the corpus callosum]. / Agenezija korpus kalozuma.

This paper presents a case of a sixteen-year-old female patient with agenesis of corpus callosum which was accidentally discovered during etiological investigation of the consciousness disorder. Agenesis of corpus callosum, a rare congenital defect, might be associated with macrocephalia and various degrees of mental impairment, optic defects, and seizures. Apart from patients with these pathologic states, there are individuals with agenesis of corpus callosum, but without any clinical disturbances.

[Clinical characteristics of speech-language dysfunctions in thalamic aphasia]. / Klinicke karakteristike govorno-jezickih disfunkcija kod talamusnih afazija.

The aim of this study was to investigate the characteristic symptom cluster and the course of aphasia in 12 patients with single left thalamic lesion verified by CAT scan. The testing of language disorder was performed by standard linguistic tests for aphasia in the acute stage and one month after the insult. Although this clinical syndrome varied greatly it was possible to point out some common characteristics. Spontaneous speech was fluent, easily articulated, grammatically correct, with preserved melodic line. Word finding and understanding were impaired. The impaired comprehension and naming were prominent in all patients with different severity. Repetition skills were intact. During the naming testing patients accomplished better results after semantic help than after phonetic help. Verbal paraphasia errors appeared more frequently (9.78) than neologistic (2.22) and literal paraphasias (1.78). Results of the language fluency tests were worse during semantic categorization tests (5.50) than during animal naming (9.89). On the basis of these facts it was presumed that aphasia in patients with dominant thalamic lesion was the result of lexicosemantic language disorder. It was statistically proved that recovery from aphasia in these cases tended to be significant and rapid.

[Therapy of lupus nephritis with standard therapeutic protocols and cyclosporine]. / Terapija lupusnog nefritisa standardnim protokolima lecenja i ciklosporinom.

The study carried out was at the Department of Nephrology, Military Medical Academy, over the period from 1996 to 2001. Different types of lupus nephritis were documented in 42 patients and were treated with standard therapeutic protocols (corticosteroids, the pulse dose of cyclophosphamide + corticosteroids) and cyclosporine in the target serum concentration of 100-120 ng/ml along with pronisone of 15-20 mg per day. The different degree of damaged renal function was observed. Renal biopsy was performed in 13 patients and in one patient rebiopsy was done. Twenty one patients were treated only with corticosteroids (remission in 23.8% of cases), with cyclophosphamide + corticosteroids 33 patients (remission in 42.4% of cases) and cyclosporine + corticosteroids 12 patients (remission in 91.7% of cases). The pulse therapy with cyclophosphamide in combination with corticosteroids, and cyclosporine in combination with lower doses of corticosteroids was statistically more successful in comparison with corticosteroids monotherapy (p < 0.01). Remission was found in 73.8% of patients, terminal renal weakness was observed in 7 patients, and fatal outcome in 4 patients. We recommend the pulse therapy of cyclophosphamide in combination with corticosteroids in the treatment of severe clinical forms of lupus nephritis, and in refractive forms cyclosporine in combination with low doses of corticosteroids.