Anxiety and Depression as Comorbidities of Multiple Sclerosis.

Multiple Sclerosis (MS), a chronic inflammatory neurodegenerative disease, is accompanied by a number of comorbidities. Among the psychiatric ones, depression and anxiety occupy a special place. It is estimated that the prevalence of anxiety in the MS population is 22.1% verus 13% in the general population; whereas the prevalence of anxiety levels, as determined by various questionnaires, reaches even 34.2%. Systematic literature reviews (SPL) show considerable data variations due to differences in study design, sample size, diagnostic criteria and extremely high heterogeneity (I2). Among the more conspicuous factors associated with anxiety disorder in MS are demographic factors (age and gender), nonsomatic depressive symptoms, higher levels of disability, immunotherapy treatments, MS type, and unemployment. Depression is the most common psychiatric commorbidity in MS and the lifetime risk of developing depression in MS patients is >50%. According to some research, the prevalence of depression in MS vary between 4.98% and 58.9%, with an average of 23.7% (I2=97.3%). Brain versus spinal cord lesions, as well as temporal lobe, fasciculus arcuatus, superior frontal and superior parietal lobe lesions in addition to the cerebral atrophy have been shown to be the anatomical predictors of depressive disorder in MS. Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and the consequent dexamethasone-insupressible hypercortisolemia, in addition to cytokine storm (IL-6, TNF-α, TGFß1, IFNγ/IL-4) present the endocrine and inflammatory basis for development of depression. Fatigue, insomnia, cognitive dysfunction, spasticity, neurogenic bladder, pain, and sexual dysfunction have shown to be additional precipitating factors in development of anxiety and depression in MS patients.

Comorbidities in Patients with Multiple Sclerosis in Croatia.

BACKGROUND: Comorbidities in multiple sclerosis (MS) have a big role in management of this chronic demyelinating neurodegenerative disorder. The aim of this study was to evaluate comorbidities in patients with MS in Croatia. SUBJECTS AND METHODS: This was a prospective cross-sectional study carried out in an out-patient setting at a tertiary healthcare centre over 10 months, which included 101 consecutive patients with MS (mean age 42.09 (range 19-77) years, 75 female, 26 male, EDSS score 3.1 (range 0.0-7.0)). The average duration of the disease was 13.5±7.487 (range 1-42) years. Thirty-six patients were treated with disease modifying therapies (DMTs). Information on comorbidities was obtained during the medical interview. Data was analysed using software package IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. RESULTS: 33% (n=34) patients did not have any comorbidities, and there is an equal number of patients (n=34, 33%) that just had one comorbidity. 17.6% (n=18) of patients had two comorbidities, and 15.7% (n=16) three or more comorbidities. The most frequent comorbidity was depression found in 25 (24.75%) patients (19 (18.8%) women, 6 (5.9%) men), followed by the hypertension in 12.87% (n=13). Hyperlipidemia and migraine were each found in 6.93% (n=7), and hypothyreosis and arrhythmia each in 3.96% (n=4). The number of the comorbidities was found to significantly increase with the duration of MS (r=0.232, p=0.037). Women were found to have significantly bigger numbers of comorbidities than men (t=-2.59, df=74, p<0.05). Older patients with MS were found to have significantly more comorbidities (r=0.335, p<0.01). CONCLUSIONS: This study gives insight into the presence of comorbidities in Croatian patients with MS. Connection with comorbidities must be considered when managing patients with MS. Any other comorbidity in MS may also affect the condition of the patient in general, and also their quality of life, and requires a tailored approach in management.

Lower Urinary Tract Symptoms and Depression in Patients with Multiple Sclerosis.

BACKGROUND: Both depression and lower urinary tract symptoms (LUTS) may be present in patients with multiple sclerosis (MS). The objective of this study was to give an insight on depression and LUTS in patients with MS in Croatia and to determine the possible association between LUTS and depression in patients with MS. SUBJECTS AND METHODS: This was a prospective cross-sectional study conducted in a tertiary healthcare center in Croatia. Hundred and one consecutive patients with MS (75 female, 26 male, mean age 42.09 (range 19-77) years, mean Expanded Disability Status Scale (EDSS) score 3.1 (range 0.0-7.0)) participated in this study. We evaluated LUTS and related quality of life (QoL) using three International Consultation on Incontinence Questionnaires (ICIQ) enquiring about overactive bladder (ICIQ-OAB), urinary incontinence short form (ICIQ-UI SF) and lower urinary tract symptoms related quality of life (ICIQLUTS-QoL). ICIQ-OAB and ICIQLUTS-QoL were for this purpose with permission successfully translated and validated into Croatian, while ICIQ-UI SF was already previously validated for the Croatian language. Information regarding treatment for depression was obtained during the medical interview. Data were analyzed and interpreted using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, N.Y., USA). RESULTS: 89.10% (N=90) patients with MS reported urgency with urge urinary incontinence (UUI) present in 70.29% (N=71). 81.18% (N=82) patients reported nocturia, and 90.09% (N=91) reported feeling drowsy or sleepy during the day due to bladder symptoms. Neurological deficit measured by EDSS was found to positively correlate with LUTS on all three questionnaires: ICIQ-OAB (r=0.390, p<0.05), ICIQ-UI SF (r=0.477, p<0.01) and ICIQ-LUTSQoL (r=0.317, p<0.05). 25 patients were in treatment for depression. There were no significant differences between female and male patients regarding treatment for depression (χ2=0.018, df=1, p>0.05). Results on ICIQ-UI SF showed that depressive patients had more pronounced LUTS (t=2.067, df=99, p<0.05), which was also true for the ICIQ-LUTSQoL (t=-2.193, df=99, p<0.05). Positive correlations were found between depression and LUTS on ICIQ-UI SF (r=0.203, p<0.05) and ICIQ-LUTSQoL (r=0.215, p<0.05). CONCLUSION: This study gives insight into the presence of depression and LUTS in Croatian patients with MS for which purpose ICIQ-OAB and ICIQ-LUTSQoL were with permission successfully translated and validated into Croatian. The connection between depression and LUTS must be considered when managing patients with MS.

Sexual Dysfunction and Depression in Patients with Multiple Sclerosis in Croatia.

BACKGROUND: Both depression and sexual dysfunction (SD) may be present in patients with multiple sclerosis (MS). OBJECTIVE: The aim of this study was to evaluate a possible association between SD and depression in patients with MS in Croatia. SUBJECTS AND METHODS: This was a prospective cross-sectional study carried out in tertiary healthcare centre over 10 months, which included 101 consecutive pwMS (mean age 42.09 (range 19-77) years, 75 female, 26 male, EDSS score 3.1 (range 0.0-7.0)). SD was assessed using Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ), which was for this purpose successfully translated and validated into Croatian. Information on treatment for depression was obtained during the medical interview. Data were analysed and interpreted using parametric statistics (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.). RESULTS: 89 patients completed MSISQ. 25 patients were in treatment for depression, while 75 did not have depressive symptoms. On MSISQ 57 (43 women, 14 men) patients had responded with 'almost always/ always' suggestive of SD. Majority of patients reported primary SD, followed by secondary and tertiary SD. Most difficulties were found regarding difficulty in getting or keeping a satisfactory erection (34.6% (N=9) men), followed by 32.9% (N=27) reporting that it takes too long to orgasm or climax, followed with bladder or urinary symptoms in 32.6% (N=29). There were no significant differences between female and male patients regarding treatment for depression (χ2=0.018, df=1, p>0.05). Results in all subcategories on t-test found that depressive patients had higher impact on SD when compared to non-depressive: overall (t=-2.691, df=87, p<0.01) and in regards to primary (t=-2.086, df=87, p<0.05), secondary (t=-2.608, df=87, p<0.05) and tertiary (t=-2.460, df=86, p<0.05) SD. Depressive patients on 7 questions showed significantly (p<0.05) higher SD symptoms: Muscle tightness or spasms in my arms, legs, or body; Tremors or shaking in hands or body; Pain, burning, or discomfort in their body; Feeling less attractive; Fear of being rejected sexually because of MS; Lack of sexual interest or desire; Less intense or pleasurable orgasms or climaxes. CONCLUSIONS: This study gives insight into the presence of depression and SD in Croatian patients with MS for which purpose valid questionnaire for the assessment of SD in MS patients MSISQ was with permission successfully translated and validated into Croatian. The connection between depression and SD must be considered when managing patients with MS.

Clinical trials in developing countries - ethical considerations.

When designing clinical trial or considering decision to take part in particular clinical trial as investigators, even before submission to responsible Central Ethic Committee, we always make certain private assessment about ethical justification of this clinical trial. When making assessment if any clinical trial is ethically justifiable, there should make no difference in which country this clinical trial will be executed. Physicians coming from developing countries must ensure that patient population of developing countries is not misused in any ethically questionable clinical trial. There must be careful assessment of clinical protocols by various independent local advisory committees (e.g. hospital review boards, hospital drug committees, hospital administration and whatever is applicable) to exclude the possibility that only one person or one group of people has concentrated power to make decisions for entire country. Many times physicians/clinical researchers from developing countries are faced with the criticisms that they are not of the same quality as physicians from developed countries and that they can be easily bribed by sponsors, which are based on the prejudice that any clinical trial can be executed in developing countries, no matter of quality or risks for patients. Physicians coming from developing countries must ensure that patient population of developing countries is not misused in any ethically questionable clinical trial.

Many Faces of Déjà Vu: a Narrative Review.

French expression standing for the phrase "already seen" is a déjà vu. It is thought that as much as 97% of the population have experienced déjà vu at least once in their lifetime and 67% experience it regularly. The explanations of this phenomenon in novels and poems include reincarnation, dreams, organic factors, and unconscious memories. In this narrative review connection between déjà vu and various other conditions has been mentioned: false memories, temporal lobe epilepsy and other neurological conditions. In psychiatric patients déjà vu phenomenon is more often seen in patients with anxiety and people with derealisation/ depersonalization. It seems that temporal region is the origin of déjà vu phenomena in both healthy individuals and in individuals with neurological and psychiatric conditions, but the exact mechanism of this phenomenon is however still unknown. More attention should also be given to déjà vu from philosophical and religious perspectives as well. Déjà vu is still an enigma which could only be revealed with multidisciplinary approach through cooperation between neurologists, brain scientists, psychiatrists and experimental psychologists.

Efficacy and safety of Ginkgo biloba standardized extract in the treatment of vascular cognitive impairment: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: The aim of this randomized, double-blind, placebo-controlled trial was to determine the efficacy and safety of Ginkgo biloba extract in patients diagnosed with vascular cognitive impairment (VCI). METHODS: A total of 90 patients (aged 67.1±8.0 years; 59 women) were randomly allocated (1:1:1) to receive G. biloba 120 mg, G. biloba 60 mg, or placebo during a 6-month period. Assessment was made for efficacy indicators, including neuropsychological tests scores (Sandoz Clinical Assessment Geriatric Scale, Folstein Mini-Mental State Examination, Mattis Dementia Rating Scale, and Clinical Global Impression) and transcranial Doppler ultrasound findings. Safety indicators included laboratory findings, reported adverse reactions, and clinical examination. RESULTS: At the end of 6-month study period, G. biloba 120 and 60 mg showed a statistically significant positive effect in comparison with placebo only on the Clinical Global Impression score (2.6±0.8 vs 3.1±0.7 vs 2.8±0.7, respectively; P=0.038). The Clinical Global Impression score showed a significant deterioration from the baseline values in the placebo group (-0.3±0.5; P=0.021) as opposed to G. biloba groups. No significant differences were found in the transcranial Doppler ultrasound findings. Adverse reactions were significantly more common and serious in the placebo group (16 subjects) than in either of the two G. biloba extract groups (eight and nine subjects, respectively), whereas laboratory findings and clinical examinations revealed no differences between the groups receiving G. biloba extract and placebo. CONCLUSION: According to our results, G. biloba seemed to slow down the cognitive deterioration in patients with VCI, but the effect was shown in only one of the four neuropsychological tests administered. However, because of this mild effect in combination with a few adverse reactions, we cannot say that it is ineffective or unsafe either. Further studies are still needed to provide unambiguous evidence on the efficacy and safety of G. biloba extract.

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

Epilepsy is the most common neurological complication in pregnancy. Women with epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy are treated by neurologists at tertiary centers according to the place of residence. We prospectively followed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factors responsible for their delivery outcomes and development of their babies. Healthy pregnant women had a higher level of education and economic status, but pregnant women with epilepsy took folic acid in a higher proportion than controls, possibly due to timely preconception counseling. Complications during pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticed some behavioral and cognitive aspects in children exposed in utero to valproic acid, which required follow up. The rate of congenital malformations was not increased. In conclusion, women with epilepsy should receive preconception counseling about the risk for pregnancy, but also about the possibilities to minimize that risk. We have introduced a model of integrative management of pregnancy and epilepsy based on close collaboration among different clinical experts in Croatia, in order to provide prompt counseling and timely intervention.

GUIDELINES FOR THE PREVENTION, DETECTION AND THERAPY OF VITAMIN D DEFICIENCY IN ADULTS.

It is estimated that over one billion of people around the globe have low serum values of vitamin D, therefore, we can consider vitamin D deficiency as a pandemic and public health problem. Geographic position of Croatia, especially the continental part of the country, is a risk factor for the development of deficiency of vitamin D in the population. The aim of these guidelines is to provide the clinicians with easy and comprehensive tool for prevention, detection and therapy of vitamin D deficienney in healthy population and various groups of patients. They were made as a result of collaboration of clinicians of different backgrounds who are dealing with patients at risk of vitamin D deficiency. These guidelines are evi- dence-based, according to GRADE-system (Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendation. The main conclusions address the recommended serum vitamin D values in the population which should be between 75 and 125 nmol/L and defining recommended preven- tive and therapeutic dosages of vitamin D in order to reach the adequate levels of serum vitamin D.

Prospective surveillance of Croatian pregnant women on lamotrigine monotherapy--aspects of pre-pregnancy counseling and drug monitoring.

We prospectively surveyed 23 pregnant women with epilepsy on lamotrigine monotherapy and reported outcome of their pregnancies, including one fetal intrauterine death, one spontaneous abortion and two preterm deliveries. There were no congenital malformations in their offspring. Women with pregnancy planning and folic acid intake delivered babies with higher values of birth weight and birth length. There was large inter-patient variation during drug monitoring and in the need of dose adjustment. Individual approach to every woman and monotherapy with minimal effective lamotrigine dose with frequent drug monitoring enhances the possibility for successful pregnancy. The management of women with epilepsy should begin with pre-pregnancy counseling. Planned pregnancy enables periconceptional folic acid supplementation. Despite the small number of cases, these data indicate that la motrigine treatment during pregnancy might be relatively safe. Larger prospective studies are needed to obtain adequate power for statistical analysis including long-term cohort studies.

Treatment of multiple sclerosis.

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system, characterized by multifocal inflammatory destruction of myelin, axonal damage and loss of oligodendrocytes. The disease is carried through two stages: inflammatory and degenerative. The most common form of disease in approximately 85% of the cases is RRMS (relapsing-remitting form). The treatment of MS is devided into: treatment of the acute phase of illness, prevention of new relapses and disease progression, and symptomatic treatment. Most of the changes in treatment of multiple sclerosis and most of the news in recent years concerning new drugs are used in the treatment of progression of the disease and prevention of disease relapses. Some of these drugs are registrated in most Europian countries and USA, and others are in various stages of research.