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Original article

The importance of asthma control test (ACT) in asthma control level assessment ...... 77 Belma Paralija

Assessing the level of dental care to the prevalence of dental caries among school children in Central Bosnia Canton ...... 81 Aida Šaban, Sead Karakaš, Orhan Šaban, Nejra Džananović, Marina Delić–Šarac, Suvada Švrakić, Ognjen Riđić

Gender comparison of serum asymmetric dimethylarginine and C-reactive protein concentration in patients with diabetes mellitus type 2 ...... 85 Asija Začiragić, Berina Hasanefendić, Nesina Avdagić, Orhan Lepara, Nermina Babić, Jasminko Huskić, Nedžad Mulabegović

Comparative analyses of the effect of surgical weakening of inferior oblique muscle overaction on binocularity ... 91 Jasmina Alajbegović–Halimić, Denisa Zvizdić, Haris Tanović

Incidence and risk factors of complications after tonsillectomy ...... 96 Lana Sarajlić, Adnan Kapidžić, Jusuf Šabanović, Haris Tanović, Igor Gavrić, Ismar Rašić

Efficiency of conservative treatment of postpartum hemorrhages caused by uterine atony ...... 99 Mohamad Abou El-Ardat, Zulfo Godinjak, Nermin Hadžić, Naima Imširija, Aida Dizdarević, Eldar Mehmedbašić, Armina Rovčanin

Psychiatric comorbidity among opiate addicts on methadone substitution treatment ...... 102 Rasema Okić

Imbalanced values of highly reactive molecule nitric oxide in schizophrenia ...... 106 Amra Memić, Abdulah Kučukalić, Lilijana Oruč, Jasminko Huskić

Epidemiological and clinical characteristics of childhood lymphoma ...... 110 Edo Hasanbegović, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić

Secondary osteoporosis in hospital sample ...... 116 Ksenija Miladinović, Narcisa Vavra-Hadžiahmetović, Slavica Šakota, Damir Čelik, Haris Tanović

Professional article

Most common etiologies of neurogenic laryngeal paralysis in middle-aged patients ...... 120 Mirjana Gnjatić, Daniela Kesić Mijić, Tatjana Barać, Svjetlana Trifunović

Surgery and endoscopic treatment in children with vesicoureteral reflux ...... 124 Murat Berisha, Nexhmi Hyseni, Salih Grajqevci, Sejdi Statovci, Ali Aliu

Blood pressure oscilation during carotid endarterectomy in superficial cervical plexus block ...... 127 Dragan Milošević, Darko Golić

Case report

Uterine anomalies and pregnancy outcome: uterus unicornis cum cornum rudimentarium ...... 130 Lejla Imširija, Naima Imširija, Mohamad Abou El-Ardat, Fatima Gavrankapetanović

Hemorrhagic fever with renal syndrome and coexisting hantavirus pulmonary syndrome ...... 132 Duško Anić, Emina Vukas, Almira Kadić

Review article

Surgical treatment of traumatic flail chest ...... 134 Dušan Janičić, Bojan Gulić, Zoran Roljić, Velibor Škrbić

Instructions to authors ...... 136

Uputstva autorima ...... 138 Medical Journal (2014) Vol. 20, No. 2, 77 - 80 Original article The importance of asthma control test (ACT) in asthma control level assessment Značaj astma kontrol testa (ACT) u određivanju kontrole astme

Belma Paralija*

Clinic of Pulmonary Diseases, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: GINA guidelines recommend asthma treatment ac- Uvod: GINA smjernice preporučuju liječenje astme u odnosu cording to asthma control level. Aim: to assess asthma control level na razinu njene kontrole. Ciljevi istraživanja: primjenom astma kon- using Asthma control test (ACT) questionnaire and FEV1 measure- trol testa (ACT) i mjerenjem FEV1 odrediti stepen kontrole astme. ment. Patients and methods: the patients diagnosed with bronchial Pacijenti i metode: u studiji su učestvovali pacijenti sa dijagnozom asthma, who attended asthma school in the period from 2010 to bronhijalne astme, a obuhvaćeni programom astma škole u periodu 2011 at the Clinic of Pulmonary Diseases, were included in this study. od 2010-2011. godine na Klinici za plućne bolesti. ACT upitnik, koji At first ACT questionnaire was self completed by patients. ACT con- su sami pacijenti popunjavali, sastavljen je od pet pitanja, a ona se tains five questions, regarding the frequency of daily symptoms, night odnose na učestalost dnevnih, noćnih simptoma astme, korištenje symptoms, reliever use, the potency of daily activities performance in inhalatora brzog djelovanja, mogućnost obavljanja dnevnih aktiv- the last 4 weeks, as well as patient asthma assessment by their own. nosti u posljednje 4 sedmice, a na kraju subjektivna ocjena astme Each answer was scored from 1 (poor control) to 5 (good control) od strane samog pacijenta. Svaki odgovor je bodovan ocjenom od and the scores were added to give a final score with a maximum of 1 (loša kontrola) do 5 (dobra kontrola), sa mogućim maksimalnim 25 points. The range of 20-24 points was considered as good asthma rezultatom od 25 bodova. Rezultat od 20-24 boda se smatrao do- control. A cutoff score of 19 or less identified patients with poorly brom, a ispod 20 bodova lošom kontrolom astme. Nakon toga je controlled asthma. Furthermore, the pulmonary function test was pacijentima urađeno ispitivanje plućne funkcije, a posebno su regis- performed, and FEV1 values in percent were particularly notified. trovane vrijednosti postignutog FEV1 u procentualnim vrijednostima. Results: 38.96% of the total number of examined patients (n=154) Rezultati: od ukupnog broja ispitivanih pacijenata (n=154) 38.96% su were males, and 61.04% females. Total asthma control (25 points) osobe muškog, a 61.04% ženskog spola. Potpunu kontrolu astme was achieved in 1.95% patients; good control in 30 patients (19.48%), (25 bodova) je postiglo 1.95% pacijenata; dobru kontrolu 30 pacije- while 78.57% of patients achieved less than 20 points, that means nata (19.48%), a rezultat ispod 20 bodova je zabilježen kod 78.57% poorly controlled asthma, which is directly in connection with the pacijenata, što podrazumijeva lošu kontrolu bolesti, koja je direkt- increased risk of asthma exacerbation. 61.04% of patients achieved no povezana sa povećanim rizikom od egzacerbacije astme. 61.04% FEV1 of 60-80% predicted values; less than 60% of FEV1 was notified pacijenata je postiglo FEV1 od 60-80%; ispod 60% vrijednost FEV1 in 28.57% of patients. FEV1 higher than 80% of the predicted values je postiglo 28.57% pacijenata, a 10.39% pacijenata FEV1 iznad 80%. was notified in 10.39% of patients. 48.76% of patients with poorly 48.76% pacijenata sa lošom kontrolom astme smatra da je njihova controlled asthma found their asthma good (4 points) and totally con- astma dobro (4 boda) i potpuno pod kontrolom (5 bodova). Zak- trolled (5 points). Conclusion: ACT questionnaire is a simple tool for ljučak: ACT upitnik je jednostavno sredstvo za praćenje kontrole assessing asthma control with/or without pulmonary function testing. astme u kombinaciji sa/ili bez testiranja plućne funkcije. Znatno sk- It rathershortens the time needed for symptom assessment, identifies raćuje vrijeme potrebno za procjenu simptoma i identificira pacijente the patients with uncontrolled asthma as well as facilitates physicians sa nekontrolisanom astmom i olakšava dalje praćenje napretka u li- ability to follow patient’s progress with treatment. ječenju pacijenta.

Key words: asthma control questionnaire, asthma control Ključne riječi: astma kontrol test, kontrola astme

INTRODUCTION ness and coughing, particularly at night or in the early morning. Asthma control is assessed by symptoms, activities of daily living Asthma is a chronic inflammatory disease of the airways that and quality of life. It also includes the likelihood of loss of control, causes recurring episodes of wheezing, breathlessness, chest tight- exacerbations, decline in respiratory function, and the side-effects 78 B. Paralija of treatment. The primary goals of asthma management are: 1) to ACT (Figure A) contains five questions, regarding the frequency achieve and maintain control of symptoms and 2) to prevent asthma of daily symptoms, night symptoms, reliever use, the potency of exacerbations. In many cases, it is also possible to improve and/ daily activities performance in the last 4 weeks, as well as patients or maintain respiratory function, to retain normal activity levels, to asthma assessment by their own. Each answer was scored from 1 prevent the development of irreversible airway narrowing and to (poor control) to 5 (good control) and the scores were added to prevent deaths from asthma. Clearly, it is also desirable to avoid give a final score with a maximum of 25 points. The range of 20-24 short and long-term adverse events from asthma medication. GINA points was considered as good asthma control. A cutoff score of 19 guidelines also recommend asthma treatment according to asthma or less identified patients with poorly controlled asthma. Further- control level (1). more, the pulmonary function test was performed, and FEV1 values ACT is a patient self-assessment tool of asthma control (2, 3). in percent were measured. ACT was developed by Nathan et al., in 2004 and was described as a patient-based tool for identifying patients with poorly controlled RESULTS asthma. ACT contains five questions, regarding the frequency of daily symptoms, night symptoms, reliever use, the potency of daily activities performance in the last 4 weeks, as well as patient asthma assessment by their own (2). Objectives of the study: to assess asthma control level using ACT and FEV1 measurement.

MATERIALS AND METHODS

The patients diagnosed with bronchial asthma, who attended asthma school in the period from 2010 to 2011 at the Clinic of Pul- ! monary Diseases, were included in this study. At first ACT question- naire was self completed by patients.

Figure 1 Sex distribution of examined patients.

The total of 154 patients were examined. Out of total number of the examined patients 38.96% (n=60) were males, and 61.04% (n=94) females. There was a significant difference in sex distribution in favour of females (χ2=7.506; df=1; p=0.006) (Figure 1).

Figure 2 Distribution of examined patients according to age groups.

Analysis of age group distribution reported that the most common age group was of 45-54 years (n=42). There was a significant differ- ence in the number of the examined patients related to the age group Figure A (χ2=23.74; df=5; p=0.001) (Figure 2). The importance of asthma control test (ACT) in asthma control level assessment 79

The total number of patients with ACT score <20 points (poor- ly controlled asthma) was 121 (100%). Of all patients with poorly controlled asthma, 48.76% (n=59) of patients found their asthma good (4 points) (n=42; 34.7%) and totally controlled (5 points) (n=17; 14.05%) (Table 1).

Table 1 Patients overall self-assessment of asthma control in the group with poorly controlled asthma (according to ACT score).

PATIENTS OVERALL NUMBER OF PATIENTS SELF-ASSESSMENT OF % n ASTHMA CONTROL Figure 3 Results of ACT questionnaire. GOOD CONTROL 42 34.71 (4 points)

The results of ACT questionnaire, that was self completed by TOTALLY CONTROLLED 17 14.05 patients, are presented in Figure 3. Total asthma control (25 points) (5 points) was achieved in 3 patients (1.95%); good control in 30 patients NOT CONTROLLED 62 51.24 (19.48%), and 121 patient (78.57% ) achieved less than 20 points, (1-3 points) that means poorly controlled asthma, which is directly in connection with increased risk of asthma exacerbation. There was a significant TOTAL (n=121) 100% difference in the number of patients according to the ACT score (χ2=141; df=1; p=0.001). DISCUSSION

Females are more affected by asthma than males as reported in the literature (4). In our study there was also significant difference in sex distribution in favour of females. The individuals over 34 years are commonly affected by asthma (4,5). ACT is a patient self-assessment tool of asthma control (2,3). ACT was developed by Nathan et al., in 2004. In their article the development of the ACT was described as a patient-based tool for identifying patients with poorly controlled asthma. Methods of the study: a 22-item survey was administered to 471 patients with asthma in the offices of asthma specialists. The specialists’ rating of asthma control after spirometry was also collected. Results: five Figure 4 Results of FEV1 values. items were selected from regression analyses. The internal consis- tency reliability of the 5-item ACT scale was 0.84. ACT scale scores 90 patients (61.04%) achieved FEV1 of 60-80% of the predict- discriminated between groups of patients differing in the specialist’s ed values; less than 60% FEV1 was notified in 42 patients (28.57%). rating of asthma control (F=34.5, p<.00001), the need for change FEV1 higher than 80% of the predicted values was notified in 22 pa- in patient’s therapy (F=40.3, p<.00001), and percent predicted tients (10.39%). There was significant differenceχ ( 2 =47.58; df=2; FEV1 (F=4.3, p=.0052). As a screening tool, the overall agreement p<0.05) (Figure 4). between ACT and the specialists’ rating ranged from 71% to 78% depending on the cut points used, and the area under the receiver operating characteristic curve was 0.77. The authors have conclud- ed that results reinforce the usefulness of a brief, easy to administer, patient-based index of asthma control (ACT is clinically validated against spirometry and specialist assessment) (2). In the literature, ACT has been reported as reliable (test-retest reliability was 0.77). Internal consistency is also proved (Cronbach’s α=0.84-0.85 (crossectionally); 0.79 (longitudinally). Test validity: it correlates with specialists’ rating of asthma control determined based on history, physical examination and FEV1. The minimally important difference is 3 points between two groups or for changes over time. Figure 5 Correlation of ACT results and FEV1 values. It has some limitations: it has a multidimensional construct, however does not include objective measures of airway caliber (6). The positive significant correlation between ACT results and In our study the positive significant correlation between ACT re- FEV1 values is presented in Figure 5, that was proved by Pearson sults and FEV1 values was proved by Pearson correlation (r=0.834; correlation (r=0.834; p=0.001). p=0.001). 80 B. Paralija

Other authors evaluated the reliability and validity of the ACT in 1) Is the diagnosis correct? 2) Are there any correctable trigger fac- a longitudinal study of asthmatic patients new to the care of an asth- tor (including occupation)? 3) Does the patient have allergic rhinitis ma specialist (the total number of patients 313). Internal consisten- (treatment of those may help asthma control)? 4) Is there patient‘s cy reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). compliance with the existing therapy? 5) Is the patient able to use Test-retest reliability was 0.77. Criterion validity was demonstrated his/her inhaler properly? by significant correlations between baseline ACT scores and base- line specialists’ ratings of asthma control (r=0.52, p<.001) and ACQ Conflict of interest:none declared. scores (r=-0.89, p<.001). Discriminant validity was demonstrated, with significant (p<.001) differences in mean ACT scores across pa- REFERENCES tients differing in asthma control, pulmonary function, and treatment recommendation. Responsiveness of the ACT to changes in asthma 1. Global Initiative for Asthma. Global Strategy for Asthma Management and Pre- control and lung function was demonstrated with significant correla- vention. Updated 2012. www.ginaasthma.org/uploads/users/files/GINA_Re- tions between changes in ACT scores and changes in specialists’ rat- port_2012_Feb09.pdf ings (r=0.44, p<.001), ACQ scores (r=-0.69, p<.001), and percent 2. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development predicted FEV1 values (r=0.29, p<.001). An ACT score of 19 or less of the asthma control test: A survey for assessing asthma control. J Allergy Clin provided optimum balance of sensitivity (71%) and specificity (71%) Immunol. 2004 Jan; 113(1): 59-65 3. Schatz M,Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma Control for detecting uncontrolled asthma. The authors proved the ACT as Test: reliability, validity, and responsiveness in patients not previously followed by reliable, valid and responsive to changes in asthma control over time asthma specialists. J Allergy ClinImmunol. 2006 Mar;117(3):549-56. in patients new to the care of asthma specialists. A cutoff score of 19 4. Kvrgić V et al. Analiza hospitalizovanih pacijenata zbog akutnog pogoršanja astme or less identifies patients with poorly controlled asthma (3). u Institutu za plućne bolesti Vojvodine. Univerzitet u Novom Sadu, Medicinski The ACT was responsive to change at the initiation of asthma fakultet, 2008. treatment and was useful for the initiation of asthma treatment (7). 5. Lee KH, Chin NK, Lim TK. Asthma in elderly-hard disease. Singapore Med J. 2000 It was recognized by the National Institutes of Health (NIH) in its Dec; 41(12):579-81. 6. Shatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P.The minimally 2007, Asthma guidelines (8). Other authors also support their use in important difference of the Asthma Control Test. J Allergy ClinImmunol. 2009 Oct; clinical decision making (9). 124(4):719-23. In the survey of other authors, 54% of New Zealand patients 7. Al Moamary MS, l-Kordi AG, Al Ghobain MO, Tamim HM.Utilization and respon- with asthma were not controlled (10). In our study 78.57% of pa- siveness of the asthma control test (ACT) at the initiation of therapy for patients tients achieved less than 20 points according to the ACT scale, that with asthma: a randomized controlled trial. BMC Pulmonary Medicine. 2012 Mar means poorly controlled asthma, which is directly in connection 26;12:14 doi:10.1186/1471-2466-12-14. with increased risk of asthma exacerbation. The researches have 8. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Expert Panel Report 3: Guidelines for showed that asking specific questions is much more likely to pick up the Diagnosis and Management of Asthma (EPR-3 2007.). NIH Item No 08-4051. uncontrolled symptoms. In reality, lots of people think their asthma http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed September is better controlled than it actually is (11). 10, 2007. In our study, of all patients with poorly controlled asthma, 9. Halbert RJ,Tinkelman DG, Globe DR, Lin SL. Measuring asthma control is the first 48.76% of patients found their asthma good (4 points) and totally step to patient management: a literature review. J Asthma. 2009 Sep;46(7):659-64. controlled (5 points). doi: 10.1080/02770900902963128. 10. TAPS NA5615-12MA. Last updated 12 March 2010. Copyright ©2010 GlaxoSmith- Kline NZ Limited. CONCLUSIONS 11. Lloyds pharmacy Online doctor. The Asthma Control Test-what is it and why use it? Version 120405. ACT is a simple tool for assessing asthma control with/or with- out pulmonary function testing. There’s positive significant correla- tion between ACT results and FEV1 values. It’s a patient-based tool for identifying patients with poorly controlled asthma (a cutoff score Reprint requests and correspondence: of 19 or less). Results reinforce the usefulness of a brief, easy to Paralija Belma, MD, PhD administer, patient-based index of asthma control, that rather short- Clinic of Pulmonary Diseases Clinical Centre University of Sarajevo ens the time needed for symptoms assessment. Clinical implications; Bardakčije 90 In a clinical setting the ACT should be a useful tool to help physicians 71 000 Sarajevo identify patients with uncontrolled asthma and facilitate their ability Bosnia and Herzegovina to follow patients’ progress with treatment. Recommendations; be- Phone: +387 33 444 343 fore alteration of drug therapy, the following should be considered: Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 81- 84 Original article Assessing the level of dental care to the prevalence of dental caries among school children in Central Bosnia Canton Procjena nivoa stomatološke njege s obzirom na rasprostranjenost karijesa kod djece školskog uzrasta u Kantonu Srednja Bosna Aida Šaban1*, Sead Karakaš2, Orhan Šaban3, Nejra Džananović4, Marina Delić–Šarac4, Suvada Švrakić5, Ognjen Riđić6

1Primary Health Center Travnik, 72270 Travnik, Bosnia and Herzegovina; 2Public Health Institute of the Central Bosnia Canton, 72270 Travnik, Bosnia and Herzegovina; 3Public Institution Hospital Travnik, 72270 Travnik, Bosnia and Herzegovina; 4Institute of Clinical Immunology, Clinical Center University of Sara- jevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina; 5Department for Quality Improvement and Safety of Health Services, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina; 6International University of Sarajevo, Management and Leadership studies, Hrasnička cesta 15, 71210 Ilidža, Bosnia and Herzegovina.

*Corresponding author

ABSTRACT SAŽETAK

By promoting the proper oral hygiene and maintaining the same, Promocijom pravilne oralne higijene i održavanje iste na- the formation of cavities, and thus, associated oral hygiene compli- stanak karijesa, a samim time i komplikacija u oralnoj higijeni, cations can be minimized. By examining the level of dental care with svodi se na minimum. Ispitivanjem nivoa stomatološke zaštite an impact on oral hygiene the important results will be obtained, uz utjecaj na oralnu higijenu dobit će se značajni pokazatelji koji which can be useful through the analysis of policies, guidelines and nam mogu korisiti kroz analizu politika, smjernica i aktivnosti u activities in promoting the oral hygiene. The study was designed promicanju oralne higijene. Istraživanje je dizajnirano kao studija as a cross-sectional study. The survey instrument was used for the presjeka. Kao instrument istraživanja bila je korištena anketa-in- survey interview and clinical examination of the mouth and teeth tervju, kao i stomatološki pregled usta i zuba za dobijanje poda- to provide data on the oral health of the examined children. The taka o oralnom zdravlju ispitivane djece. Izvršilo se anketiranje Survey instrument consisted of observation units in selected schools svih jedinica posmatranja u izabranim školama i u etapi izbora u in the stage of choice within these departments-selected groups of okviru njih izabrana odjeljenja-skupina učenika. Ovo istovreme- students. At the same time, this suggested our decision to use the no znači opredjeljenje za primjenu dvoetapnog stratifikovanog application of two-phased stratified sample of compatible groups. uzorka kompatibilnih skupina. Izvršen je stomatološki pregled i A dental examination was carried out and the survey of 804 prima- anketiranje 804 učenika osnovnih škola, pri čemu je 355 učeni- ry school students, where 355 students were from the urban and ka iz urbanih škola, a 449 učenika iz ruralnih škola. Dobijeni su 449 students from the rural schools. The obtained results showed rezultati koji govore da je vrijednost KEP indeksa u osnovnim that, in elementary schools in Central Bosnia Canton, the “Decayed, školama na području Srednjobosanskog kantona prilično ujedna- Missing and Filled Teeth” (abr. DMFT) index was fairly uniform. Ac- čena. Prema rezultatima ispitvanja možemo vidjeti da je broj po- cording to the results of examinations, we could see that the num- sjeta zubaru mnogo češći kod ispitanika iz urbane nego iz ruralne ber of visits to the dentist was more common, among respondents, sredine, što može biti u direktnoj vezi s izjavama i rezultatima iz from urban than the rural areas. This finding can be directly related dijela o socioekonomskom statusu, gdje smo imali odgovore o to statements and results from the part of the socio-economic sta- dostupnosti i blizini posjete zubaru kao i posjedovanju automo- tus, where we had the answers on the availability of and closeness bila i finansijskim mogućnostima koje su mnogo manje u rural- to the dentist, as well as the possession of automobile and financial nim sredinama nego urbanim. Najveći broj ispitanika izjavio je capabilities, all of which were much less prevalent in rural areas than da se plaši posjete stomatologu, što predstavlja izuzetan zdrav- urban. The largest number of respondents stated that they feared stveno-promotivni problem koji zdravstveni profesionalci iz ove dental visits. This finding represents a remarkable health-promotion oblasti moraju analizirati i dalje unapređivati. problem, which we, as health /dental care workers and the society, as a whole, must further analyze and improve upon.

Key words: prevention, dental caries, school children Ključne riječi: prevencija, zubni karijes, školska djeca 82 A. Šaban et al.

INTRODUCTION may vary, such as: enamel caries or the start of the first degree car- ies. The effects of acids that form the first fermentation are subject Dental caries is a chronic disease that progresses very slowly to organic substance enamel. As the result of this process, we can and the symptoms are difficult to detect. Sometimes it takes a year notice the lime-white dot that is clearly different from the surround- from the start of the process, until the first symptoms occur. Fi- ing yellowish-white healthy tissue. At this stage, the sensitivity to nally, the decay of tooth is manifested at the affected substances physical stimuli, such as, cold, hot, sour and/or sweet does not exist (i.e. enamel, dentin and tooth root) (1). From the idea that worms or is very weak. This decay of enamel occurs in fissures and pits or caused tooth decay, which occurred 200 years before Christ, until on the smooth surfaces of teeth. Dentine caries is the second level today, there were numerous theories about the process of decay. of caries. The most common cause of the spread of the process Today, it is considered that the caries disease is caused by many is enamel. It manifests itself as a relatively narrow opening in the different organisms, most notably Streptococcus mutants’. enamel, which covers the edges of a cavity in dentin. Dentin damage Important epidemiological evidence links Streptococcus mu- consists of a cavity that is formed due to the loss of tissue. Softened tants with caries. The numerous laboratory studies have shown the dentin is free of mineral salts and its organic structure is changed ability of these types of streptococci to produce lactic acid, which by the microbes (7). In this dentin we can detect the presence of causes demineralization of enamel (2). Dental plaque plays an im- various types of microorganisms, such as, lactobacilli or micrococ- portant role in caries development, which is a soft, hard discernible cus. The so-called zone invasion occurs as amended, below softened layer, which firmly adheres to the wall of the tooth. Since the pa- dentin zone or in the area of ducts filled with microbes and tissue tient cannot wash it off, it must be mechanically removed. Plaque that are completely softened and destroyed. Dentine caries can ex- begins to form immediately after tooth brushing. First, it creates a ist without subjective complaints. It is revealed by careful examina- thin surface coating (called “pellicle”), which becomes inhabited by tion or by the sensitivity to cold, less warm and moderately sour and bacteria. Bacteria develop using the metabolic products and other sweet food or water. Penetrating cavities in some cases represent a ingredients from saliva and food. Full plaque formation ends in about rapid evolution in the direction of the pulp and reach fast the pulping seven days (3). By exploiting carbohydrates, the bacteria in dental chamber. This flow of decay is seen in dairy and permanent teeth. plaque produce acids, which in contact with the enamel leads to its Cavities are usually localized to premolar and molar fissure. Circular demineralization. decay is a special type of dental caries, in its course, localization and At the beginning, while still working on immature plaque (i.e. outcome. It occurs in young children, as early as the second year of somewhat clean teeth), it is possible that the processes of regen- age. It covers dairy upper front teeth. It starts on the labial surfaces eration or enamel re-mineralization can occur by the various saliva as the murky green stain that spreads circularly around the neck of ingredients. De-mineralization and re-mineralization processes take the tooth, and dentin, and then continues to completely destroys place until the plaque is not mature. Mature plaque, on one hand, the crown of the tooth. It is very likely caused by the frequent effect prevents the flow of saliva to the teeth, and on the other hand, of carbohydrates (i.e. sweetened dummy) and various endogenous does the same to the inside of plaque. Bacteria can reach the small and exogenous influences. If left untreated, it spreads to the pulp molecules of sucrose (sugar), which acidic decomposition products and leads to its illness. The further progress of the disease may lead maintain the degree of plaque acidity (pH), with the critical value of to changes at the top of the tooth root and damage to the sur- 5.2, which favors the formation of dental caries (eng. carries gen- rounding tissue (8). Treatment consists of preventing caries and it esis). The result is irreversible enamel de-mineralization, in other plays a significant role in a way to take care of the mouth and teeth. words, this represent compensatory mechanisms within the oral Wash your mouth and teeth using toothbrush and toothpaste, in the cavity, which cannot be treated. This development marks the be- morning and evening, preferably after each meal. It is useful to know ginning of creation of initial caries lesions (initial damage) (4). Tooth that if sugar remains long in contact with the teeth, it causes caries. decay is caused by damage to the hard bone tissue, which leads to The preventive measures include early detection of initial damage, their softening and destruction. A child is born with a sterile oral which is why it is recommended to have a dental check-up every six cavity. Colonization of the oral environment microorganisms must months, or at least once a year (9). be prevented because they are normal inhabitants of the oral cavity and are responsible for the development of the immune system of MATERIALS AND METHODS the child. Streptococcus mutants group, to inhabit the eruption of the first teeth, are usually transmitted directly from mother to the child (vertical transmission) (5). Cavities can also be called a dental To test the level of dental care unit we used the questionnaire disease that begins at the surface and spreads to the core, or pulp, and dental examination. We surveyed 804 students in elementa- and it is reflected in the gradual destruction of enamel and then the ry school, where 355 students were from the urban schools and dentin. Factors that cause tooth decay, as well as the theory that 449 students from the rural schools. The study was designed as a explains the origin and evolution suggest that caries may be close- cross-sectional study. The survey instrument was used for the sur- ly related to the general state of the organism (6). New theories vey interview and clinical examination of the mouth and teeth to about the origin of caries explain the resistance of tooth decay in the provide data on the oral health of children examined. The survey presence of physiological balance in the system of blood-tooth-sa- was comprised of observation units in selected schools at the stage liva. If you damage the function of this system, which is unique, as a of choice, within these departments-selected groups of students. whole, you will create a new pathological condition - dental caries. We also utilized a two-phased stratified sample of compatible The anatomical-morphological and pathological and clinical terms groups. Assessing the level of dental care to the prevalence of dental caries among school children in Central Bosnia Canton 83

Planned pattern in all municipalities was satisfactorily achieved. According to the table listed above, we can see that the DMFT In general, all elections units were covered by the sample. The units index, in elementary schools in Central Bosnia Canton was fairly uni- of analysis, as seen from the sample project, were envisaged as a form. The lowest value of 2.9, in girls, was measured at the Primary random expected size, and therefore the realization of samples of school Guča Gora – Travnik, while the girls in elementary school at special importance for each analytical unit was achieved. Kalibunar had the largest value of 4.8. KEP value index. In boys, that In addition to numerical methods in the analysis of the results of value was the largest at the elementary school in Travnik, with the this study graphical analysis methods were also used, namely: measured value of 4.4, while the youngest boys from the Primary - Bar charts, horizontal and vertical parallel to the presentation of school at Vitovlje, had the value of 3.3. the structure and characteristics within and between individual municipalities, DISCUSSION - Circular charts for displaying the structure, - Combination charts for showing the structure of those units of By posing a group of questions related to the status of oral hy- analysis that have analyzed characteristic, giene in patients we received the insights about their state of oral - Graphs to show the confidence interval for the probability milieu. Therefore, we could clearly see that a large number of re- p=95%, in which we should expect that it will move its value in spondents had not learned how to wash their teeth properly and the basic group and the obtained values from the sample. how to maintain the oral hygiene. A large number of respondents Work methods and plan of action: had already visited the dentist, but on average 1-3 times. This find- 1. Creation of questionnaires and publicity materials and ing represents a very worrying fact that a large number of respon- 2. Education of working team members. The members were fa- dents from the urban areas visited a dentist in the projects 7-9 times, miliar with the available data on oral hygiene habits and their compared to significantly less number by children from rural areas. impact on oral health, various techniques and tools for proper Fear of the dentist was observed in both groups in the same pro- oral hygiene, and tools and techniques for the determination of portion. A disturbing fact was that a very small number of respon- OHI (index oral hygiene). dents received any advice from a dentist or some pharmacological 3. Data were collected by conducting surveys in classrooms (one substances to improve the oral hygiene milieu. Poor enlightenment class from each age group selected within primary schools) and and promotion of oral hygiene certainly affected the answers to the filling out questionnaires with the assistance of members of the question of how many times a day the respondents brushed their survey team in order to help determining the status and oral teeth, and the largest number of respondents reported twice a day, hygiene index. while the large number of respondents from the urban areas made 4. At the end, data analysis and evaluation was performed. irregular oral hygiene milieu (10). Oral hygiene habits among prima- ry school students cannot receive the most positive assessment, due RESULTS to the fact that the answers and the results of the survey showed otherwise (11). As the important factor can be considered a large Assessment of the level of dental care was conducted on the number of unenlightened subjects, 18.25% in the urban environ- basis of dental surveys carried out at urban schools in Travnik, Kali- ment, which stated that they were not familiar with regular brushing bunar, then in rural schools in Guča Gora, Turbe, Mehurići, Karaula and nobody showed them the proper way of brushing (12). As a and Vitovlje. It was based on KEP index, the number of healthy teeth predominant factor in this troubling development could also be con- with fillings, extracted teeth, as well as the insight into the state of sidered a poor oral hygiene promotion, due to the large number of oral hygiene of each child. On the basis of responses to a group of respondents who were not familiar with the means to strengthen questions related to the method of maintaining daily oral hygiene, teeth totaling 79.62% (out of which 35.5% from the urban areas and the number of visits to the dentist, knowledge of proper brushing, 44.12% from the rural areas) (13). and generalized oral hygiene, the following results were obtained: CONCLUSION Rural areas 1 – 10% 2- 25% 3 – 45% 4 – 15% 5 – 5% Urban areas 1 – 15% 2 – 15% 3 – 55% 4 – 15% 5- 10% According to the examinations’ results, we could clearly see that

Table 1 Summary overview of analyzed data. the number of visits to the dentist was more common among re-

Fissures spondents from the urban than the rural areas, a finding which can Elementary School (E.S.) Sex Caries Filings Extractions sealed DMFT M 184 310 316 184 18 4,4 be directly related to statements and results linked to respondents’ E.S. ¨TRAVNIK¨ Travnik Ž 142 213 206 162 9 4,1 socio-economic status, where we had the answers on the availability E.S. ¨KALIBUNAR¨ Travnik, M 23 37 35 25 2 4,2 Total: 29 of dental services and closeness to the dentists, as well as having a Ž 6 11 9 9 0 4,8 E.S. ¨Kar M 29 43 47 30 0 4,1 motor vehicles and financial capabilities that were much less avail- ula¨ Travnik, Total: 48 Ž 19 28 32 19 0 4,1 M 29 47 43 32 1 4,2 able in the rural, as opposed to the urban areas. Most of the respon- E.S. ¨Guča Gora¨ Travnik Total 55 Ž 26 32 28 16 0 2,9 dents stated that they feared dental visits, which poses a remarkable M 88 148 132 82 0 4 E.S. ¨Turbe¨ Travnik Total: 145 Ž 57 86 95 57 0 4,1 health-promotion problem, on which the scientists and legislators

E.S. ¨Vi M 22 26 26 22 0 3,3 must conduct a further research and information campaigns in order ovlje¨ Travnik Total 45 Ž 32 36 33 30 1 4,5 M 80 105 116 84 0 3,8 to further analyze and improve the overall state of the oral health. E.S. „Mehurići“ Travnik Total 156 Ž 76 73 79 84 0 3,2 Most of the respondents in both urban and rural areas stated that 84 A. Šaban et al. no one had addressed a diet supplements or educated about proper 9. Rediu SC, Antohe ME, Maxim A. Epidemiological aspects of frontal indentation of nutrition, which helps in developing teeth and preservation of good children’ and adolescent teeth. Rev Med Chir Soc Med Nat lasi. Romania: 2010 Apr oral hygiene. – Jun;114 (2):542-6. 10. Wang SJ, Briskie D, HuJ C, Majewski R, Inglehart MR. Illustrated information for parent education: Parent and patient responses. Pediatr Dent. 2010 July – Aug; 32 Conflict of interest: none declared. (4): 295-303. 11. Fontana M, Young DA, Wolff MA, Pitts NB, Longbotttom C. Defining dental caries REFERENCES for 2010 and beyond. Dent Clin North Am. 2010 Jul; 54(3):423-40. 12. Page J., Weld JA, Kidd EA. Caries control in health service practice. Br Dent J. 2010 1. Stojanović N, Krunić J. The prevalence of dental caries among adolescents in East- May 22; 208(10):449-50. ern Bosnia - Foča municipality. Remnant. 2006; 53 (4): 229-235. 13. Sheiham A, Sabbah W. Using universal patterns of caries for planning and evaluating 2. Jurić H. Caries preventive agents (Part I). Croatian Dental Journal. 2003;2: 6-8. dental care. Caries Res. (2010);44 (2):141-50. 3. Jurić H. Caries preventive agents (II part). Croatian Dental Journal. 2003; 3,:11-4. 4. Koch G, Poulsen S, Tweetman S. Caries prevention in child dental care: Pediatric dentistry - A clinical approach. Copenhagen: Blackwell Munkgaard; 2003. pp. 119- 45. 5. Ciglar I, Škaljac G, Šutalo J. Caries prevention – pathology and therapy for the hard Reprint requests and correspondence: dental tissues. U: Patologija i terapija tvrdih zubnih tkiva; 1994. pp. 231-40. Aida Šaban, DMD 6. Petersen PE, Lennon MA. Effective use of fluorides for the prevention of dental Primary Health Care Center Travnik caries in the 21st century: the WHO approach. Community Dent Oral Epidemiol. Vezirska 1 2004; 32: 319-21. 72270 Travnik 7. Twetman S, Ekstrand K, Qvist V, Ugeskr L. Dental caries in an ecological perspec- tive. Danish. Ugesker Laeger. 2010 Nov 1; 172 (44): 3026-3029. Bosnia and Herzegovina 8. Cashmore AW, Phelan C, Blinkhorn AS. Dental caries in children. NSW Public Phone: +387 61 848 698 Health Bull. 2010 Jul-Aug; 21 (7-8):184-5. Email: [email protected]

Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Medical Journal (2014) Vol. 20, No. 2, 85 - 90 Original article Gender comparison of serum asymmetric dimethylarginine and C-reactive protein concentration in patients with diabetes mellitus type 2 Spolna usporedba koncentracije asimetričnog dimetilarginina i C-reaktivnog proteina u serumu pacijenata sa dijabetes melitusom tip 2 Asija Začiragić1*, Berina Hasanefendić2, Nesina Avdagić1, Orhan Lepara1, Nermina Babić1, Jasminko Huskić1, Nedžad Mulabegović3

1Department of Human Physiology, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina, 2Department of Clinical Chemistry and Biochemistry, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 3Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herze- govina.

*Corresponding author

ABSTRACT SAŽETAK

Previous studies have shown that asymmetric dimethylarginine Prethodne studije su pokazalale da asimetrični dimetilarginin (ADMA) as a marker of endothelial dysfunction, and C-reactive pro- (ADMA) kao marker endotelne disfunkcije i C-reaktivni protein tein (CRP) as a marker of chronic low-grade inflammation have signifi- (CRP) kao marker hronične inflamacije niskog stepena imaju znača- cant impact on development and progression of cardiovascular disease jan uticaj na razvoj i progresiju kardiovaskularnih bolesti (KVB), kao (CVD), and on diabetes mellitus-associated vascular impairment. Fur- i na dijabetes-povezana vaskularna oštećenja. Nadalje, studije su po- thermore, studies have shown increased CVD risk in diabetic women kazale povećan rizik od KVB kod žena u poređenju sa muškarcima compared to diabetic men but overall reasons for greater augmentation sa dijabetes melitusom tip 2 (DMT2) iako opšti razlozi povećanja KV of CVD risk in diabetic women are still not fully understood. The aim of rizika kod žena sa DMT2 još uvijek nisu u potpunosti shvaćeni. Cilj the present study was to conduct gender comparison of serum ADMA ove studije bio je provesti spolnu usporedbu koncentracije ADMA i and CRP concentration in type 2 diabetic patients as well as in healthy CRP u serumu pacijenata sa DMT2, kao i kod zdravih ispitanika. Kon- subjects. Serum ADMA concentration was determined by ELISA meth- centracija ADMA u serumu određena je ELISA metodom, a koncen- od and high-sensitivity CRP was determined by immunonephelometry in tracija visoko-senzitivnog CRP u serumu je određena imunonefelo- 60 patients (30 male, 30 female) with diabetes mellitus type 2 (DMT2) metrijom kod 60 pacijenata (30 muškaraca, 30 žena) sa DMT2 i 60 and in 60 healthy individuals (30 male, 30 female). Results of our re- zdravih osoba (30 muškaraca, 30 žena). Rezultati našeg istraživanja search have shown increased serum ADMA concentration in female su pokazali povećanu koncentraciju ADMA u serumu pacijentica sa compared to male patients with DMT2 (p=0.011). Likewise, statistically DMT2 u poređenju sa pacijentima oboljelim od DMT2 (p=0.011). significantly higher ADMA concentration was determined in female com- Također, statistički signifikantno veća koncentracija ADMA određe- pared to male control subjects (p=0.028). In female patients with DMT2 na je u serumu ispitanica u poređenju sa ispitanicima kontrolne we determined significantly higher serum CRP values compared to male grupe (p=0.028). U serumu pacijentica sa DMT2 utvrdili smo sig- patients with DMT2 (p=0.001). Moreover, significant increase in serum nifikantno veću koncentraciju CRP u poređenju sa pacijentima obol- CRP levels was observed in female compared to male healthy control jelim od DMT2 (p=0.001). Signifikantan porast koncentracije CRP u subjects (p=0.017). Results of the present study have shown higher serumu opažen je i kod ispitanica u poređenju sa ispitanicima kon- values of serum ADMA and CRP concentration in female compared trolne grupe (p=0.017). Dobijeni rezultati sugeriraju da bi izraženija to male patients with DMT2. Obtained results suggest that more pro- endotelna disfunkcija i hronična inflamacija niskog stepena kod žena nounced endothelial dysfunction and chronic low-grade inflammation in u poređenju sa muškarcima sa DMT2 mogla biti jedno od mogućih diabetic women compared to diabetic men could be one of the possible objašnjenja povećanog kardiovaskularnog morbiditeta i mortaliteta explanations for increased cardiovascular morbidity and mortality in fe- kod pacijentica oboljelih od DMT2. Longitudinalne studije sa većim male patients with DMT2. Longitudinal studies with larger sample size uzorkom ispitanika su neophodne u cilju potvrđivanja opaženih nala- are warranted for the confirmation of the observed findings. za.

Key words: asymmetric dimethylarginine, C-reactive protein, en- Ključne riječi: asimetrični dimetilarginin, C-reaktivni protein, en- dothelial dysfunction, gender, diabetes mellitus type 2 dotelna disfunkcija, spol, dijabetes melitus tip 2 86 A. Začiragić et al.

INTRODUCTION profile and achieved therapeutic goals less frequently than did men. Conversely, results from the Barbanza Diabetes study showed no Asymmetric dimethylarginine (ADMA) is a naturally occurring difference in medium-term prognosis, with regard to mortality and endogenous inhibitor of nitric oxide (NO) synthase (1). Defined cardiovascular morbidity, between male and female diabetics from referent values of ADMA in blood are in a range from 0.36 to 1.17 the same geographical area, despite the presence of clinical differ- μmol/L and gender dependent correlation between ADMA and age ences between the sexes (15). Currently, the influence of gender on has been shown (2). CVD morbidity and mortality especially in diabetic patients remains Since its discovery in 1992 many features of ADMA properties one of the most controversial medical topics. have been reported but the most significant one remains reduction Majority of studies reported increased ADMA and CRP con- of NO production which consequently leads to endothelial dys- centration in patients with DMT2 (16, 17). However, studies that function. Results of numerous studies conducted in recent years investigated influence of gender on serum ADMA and CRP level in have demonstrated that endothelial dysfunction has central role in patients with diabetes mellitus are limited. Thus, the aim of the pres- pathophysiology of atherosclerosis (3). In many of those studies ent study was to conduct gender comparison of serum ADMA and ADMA was used as non-invasive marker of endothelial dysfunction. CRP concentration in type 2 diabetic patients as well as in apparently Increased plasma value of ADMA has been associated with hyper- healthy subjects. tension, hypercholesterolemia, insulin resistance and diabetes. Fur- thermore, in the last decade ADMA has been suggested as potential MATERIALS AND METHODS cardiovascular risk factor (4). C-reactive protein (CRP) is currently most studied and best val- Subjects: we recruited 60 patients with diabetes mellitus type idated biomarker of inflammatory processes. In a study by Shine et 2 (30 male, 30 female), as defined by American Diabetes Associ- al. (5) determined median serum CRP concentration in healthy adult ation (18), who regularly attend the Out-Patient Family Medicine volunteer blood donors was 0.8 mg/L, the 90th percentile was 3.0 Clinic „Višnjik“ in Sarajevo. All patients were receiving antidiabetic mg/L, and the 99th percentile was 10 mg/L. Majority of studies and antihypertensive therapies and some were receiving antilipid- have confirmed that age, gender and body mass index have influence emic drugs and/or aspirin for at least 6 previous months. Exclusion on CRP basal concentration (6). criteria was the presence of sustained acute and chronic infections, Measurement of CRP considerably contributes to monitoring malignancy, hepatic or renal disease, diabetic retinopathy and ne- of the response on inflammation and infection treatment, screening phropathy, and other endocrine dysfunctions. The control group of organ diseases, as well as in detection of infection in immunosu- consisted of 60 apparently healthy subjects (30 male, 30 female) pressed individuals (7). Recent findings have also shown importance with no history of DMT2, other endocrine dysfunctions, hyperlipid- of CRP as a marker of systemic low-grade inflammation. This chron- emia, hypertension, or coronary heart diseases. None of the con- ic condition is characterized by moderate CRP increase in blood trol subjects had received any medication (hormone replacement without classical signs of inflammation. Numerous metabolic diseas- therapy, corticosteroids, vitamin supplements, antioxidant formu- es that are annotated with cellular stress and metabolic dysfunction lations and thiazolidinediones) which might affect insulin resistance are frequently accompanied by chronic low-grade inflammation (8). and/or endothelial function and none of the subjects were current Furthermore, majority of studies have confirmed important role of smokers and consumers of alcohol. CRP in cardiovascular risk assessment. According to existing guide- Blood sampling: blood was collected in the morning after an lines, individuals with CRP values < 1 mg/L are considered to be in overnight fast after a 30-min rest in a semi-recumbent position. Sam- low, those with CRP values 1-3 mg/L in moderate and those with pling was done without stasis, using the vacutainer technique. CRP values > 3 mg/L in high cardiovascular risk (9). Blood chemistry analysis: serum ADMA concentration was de- It is now widely accepted that endothelial dysfunction and termined by ELISA method (machine STAT FAX 2100, USA) at the chronic low-grade inflammation have pivotal impact in diabetogen- Department of Physiology and Biochemistry, Faculty of Medicine esis. Impaired endothelium-dependent vasodilatation has been in- University of Sarajevo. ADMA ® - ELISA kit (DLD Diagnostika variably demonstrated in patients with diabetes. This is partly due GmbH, Hamburg, Germany) was used as reagent. ADMA standards to the frequent association of this disease with other cardiovascular range from 0.1 to 5.0 µmol/L and the detection limit for ADMA risk factors, including obesity, dyslipidemia and hypertension. Based with the use of this method is 0.05 µmol/L. Serum CRP was de- on recent reports, mechanisms leading to endothelial damage in di- termined particle- enhanced immunonephelometry with the use of abetes, independent of the damage due to other cardiovascular risk BN II analyzer. CardioPhase high-sensitivity CRP (DADE BEHRING, factors include insulin resistance, hyperglycemia, as well as systemic Marburg, Germany) was used as a diagnostic reagent. CardioPhase low-grade inflammation (10). hs-CRP consists of a suspension of polystyrene particles coated Higher risk of cardiovascular disease in adult diabetics than in with mouse monoclonal antibodies to CRP. Reference interval for the general population of the same age has been well document- CRP with the use of this method is from 0 to 5 mg/L, and the lower ed (11). Although many studies indicate that female diabetics are at limit of CRP detection is 0.18 mg/L. The total cholesterol (TC), greater CVD risk and mortality than male diabetics, the relative risk HDL-cholesterol (HDL-C), and triglyceride levels were measured varies among studies, and the basis for the sex difference remains with the use of standard enzymatic methods. The LDL-cholester- inconclusive (12, 13). ol (LDL-C) levels were calculated using the Friedewald formula. Recent study by Kautzky-Willer et al. (14) reported that women Glycated hemoglobin (HbA1c) was measured by an immunotur- with diabetes mellitus type 2 (DMT2) had worse cardiovascular risk bidimetric method (TINIA; Siemens Healthcare Diagnostics Ltd, Gender comparison of serum asymmetric dimethylarginine and C-reactive protein concentration in patients with diabetes 87

Camberley, United Kingdom). Normal range was 4.8-6.0%. All bio- and female subjects of the control group in values of BMI, WHR chemical tests, except for ADMA determination, were performed and DBP (p<0.05). Significant difference in values of fasting glucose, at the Department of Clinical Chemistry and Biochemistry, Clinical total cholesterol, triglycerides, LDL-cholesterol and HDL-cholester- Center University of Sarajevo. ol between male and female subjects of the control group was not BMI, WHR and BP measurements: height was measured with observed. In patients with diabetes mellitus type 2, female patients stadiometer and weight with a Toledo self-zeroing weight scale. had higher values of SBP and LDL-cholesterol compared with to From these two measurements, Body Mass Index (BMI) for each male diabetic patients (p<0.05). Significant difference in age and in subject was calculated (weight in kilograms divided by height in values of BMI, WHR, DBP, fasting glucose, glycated hemoglobin, square meters). To determine waist to hip ration (WHR), the stan- total cholesterol, triglycerides, and HDL-cholesterol between male dardized clinician tape was placed around the narrowest part of the and female patients with type 2 diabetes mellitus was not observed. waist and then placed around the widest part of the hips. The ratio Data are presented as mean ± SEM. CG men: control group was determined by dividing the waist measurement by the hip mea- men; CG women: control group women; DMT2 men- male patients surement. Three supine blood pressure recordings were made after with diabetes mellitus type 2; DMT2 women- female patients with a 5-min rest using an Omron 705c oscillometric device. The mean of diabetes mellitus type 2. BMI: Body Mass Index; WHR: waist-hip the second and third readings was used. Hypertension was defined ration; SBP: systolic blood pressure; DBP: diastolic blood pressure; as having a systolic blood pressure (SBP) ≥ 140 mmHg and/or a FG: fasting glucose; HbA1c: glycated hemoglobin; TC: total choles- diastolic blood pressure (DBP) ≥ 90 mmHg. terol; TG: triglycerides; HDL-C: HDL-cholesterol; LDL-C: LDL-cho- The study was approved by the Ethics Committee of the Med- lesterol. ical Faculty University of Sarajevo. Written informed consent was ∆ p<0.01 – compared to male control subjects obtained from all subjects. Investigations were carried out in accor- § p<0.05 – compared to female control subjects dance with the Declaration of Helsinki as revised in 2000. ◊ p<0.05 – compared to male control subjects Statistical analysis: Shapiro -Wilk normality test was used to test • p<0.05 – compared to male diabetic patients the distribution of variables. Normally distributed data are present- Figure 1 shows the median and inter-quartile range of serum ed as mean ± SEM and skewed variables as median and interquartile ADMA concentration in male subjects of the control group (0.60; ranges. An unpaired Student t-test or Mann-Whitney U-test was 0.50-0.70 μmol/L) and in female subjects of the control group (0.70; used to compare the difference between two groups, as appropri- 0.57-0.80 μmol/L). Serum ADMA concentration in female subjects ate. A p value of less then 0.05 was considered statistically signifi- of the control group was statistically significantly higher compared cant. The software used was SPSS for Windows (version 17.0; SPSS, to male subjects of the control group (p=0.028). Furthermore, the

Chicago, IL, USA). median! and inter-quartile range of serum ADMA concentration in

RESULTS

The basic characteristics of the study participants by gender are reported in Table 1. Statistically significant difference was observed between male and female subjects of the control group in age and in values of SBP and glycated hemoglobin (p<0.01). Furthermore, statistically significant difference was also observed between male

Table 1 Summary overview analyzed data. Gender com- parison of basic characteristics in controlling subjects and patients with diabetes mellitus type 2.

CG men CG women DMT2 men DMT2 women Variables n=30 n=30 n=30 n=30

Age 49.97±1.37 58.40±0.92 56.26±1.29 57.10±1.18 (years) § BMI2 29.04±0.45 27.68±0.45 31.03±0.83 29.88±1.02 Figure 1 Serum asymmetric dimethylarginine concentra- (kg/m ) tion in male and female subjects of the control group and WHR 0.84±0.02 0.89±0.01 0.94±0.01 0.93±1.01 in male and female patients with diabetes mellitus type 2. SBP 117.47±2.40 133.33±3.02 134.50±2.55 142.83±2.86 (mmHg) male patients with diabetes mellitus type 2 (1.45; 0.90-1.70 μmol/L) DBP 78.83±1.23 83.67±1.45 83.00±1.61 86.17±1.53 (mmHg) and in female patients with diabetes mellitus type 2 (1.65; 1.20-2.00 FG 5.25±0.14 5.42±0.15 8.90±0.49 8.16±0.59 (mmol/L) μmol/L) are also presented in Figure 1. Serum ADMA concentra- HbA1c 5.49±0.04 5.78±0.49 7.48±0.23 7.33±0.28 (%) tion in female diabetic patients was statistically significantly higher TC 5.68±0.18 5.30±0.19 5.76±0.16 5.89±0.17 compared to male diabetic patients (p=0.011). (mmol/L) The solid horizontal lines denote the median value, the box TG 1.65±0.14 1.64±0.14 2.30±0.19 2.76±0.24 (mmol/L) represents the 25% and 75% inter-quartile ranges and the whiskers HDL-C 1.34±0.06 1.35±0.05 1.16±0.06 1.13±0.05 (mmol/L) represent minimum and maximum values. LDL-C 3.57±0.15 3.51±0.19 3.57±0.17 4.06±0.18 (mmol/L) CG male – male subjects of the control group (n=30) CG female – female subjects of the control group (n=30) 88 A. Začiragić et al.

DMT2 male – male patients with diabetes mellitus type 2 (n=30) concluded that beginning of menopause in women results in signif- DMT2 female - female patients with diabetes mellitus type 2 icant increase of serum ADMA levels. Furthermore, clinical studies (n=30) reported lower ADMA values in postmenopausal women who were * - compared to male subjects of the control group taking hormonal supplement therapy with estrogens (19). ! ** - compared to male patients with diabetes mellitus type 2 Results of our research have shown increased serum ADMA p - probability concentration in female compared to male patients with DMT2. Likewise, higher ADMA concentration was determined in female compared to male control subjects. The mean age of our female DMT2 patients was over 50, so our results confirm influence of menopause on ADMA increase in women compared to men of the same age group. None of our female DMT2 patients have taken hormonal supplement therapy so we exclude possible influence of estrogens on the obtained results. ! Given that the influence of gender on serum ADMA concen- tration in patients with DMT2 has not been extensively investigated so far we are limited in comparison of our results with the results of other authors. However, recent study by Anderssohn et al. (20) reported that sex was independent determinant of plasma ADMA concentration in patients with DMT2. Interestingly, findings of this study did not support previously reported associations or causal re- lationship between ADMA and features of diabetes or cardiovascu- Figure 2 Serum C-reactive protein concentration in male lar disease. and female subjects of the control group and in male and female patients with diabetes mellitus type 2. Significantly higher serum CRP concentration, as well as other proinflammatory markers, has been found in women with metabolic Figure 2 shows the median and inter-quartile range of serum syndrome compared to men with the same condition. In healthy CRP concentration in male subjects of the control group (0.75; subjects included in this study gender difference in serum CRP con- 0.47-1.60 mg/L) and in female subjects of the control group (1.50; centration was not observed (21). Hu et al. (22) investigated wheth- 0.87-2.72 mg/L). Serum CRP concentration in female subjects of er gender had influence on association between CRP and risk for the control group was statistically significantly higher compared to diabetes development. Results of this study have shown that high male subjects of the control group (p=0.017). Furthermore, the CRP levels are associated with increased risk for DMT2 both in men median and inter-quartile range of serum CRP concentration in and in women, but this association was more markedly present in male patients with diabetes mellitus type 2 (1.20; 0.70-3.52 mg/L) women. Saltevo et al. (23) reported increased serum CRP concen- and in female patients with diabetes mellitus type 2 (4.10; 1.57-8.15 tration in women compared to men with DMT2. mg/L) are also presented in Figure 2. Serum CRP concentration in In female patients with DMT2 we have determined significantly female diabetic patients was statistically significantly higher com- higher serum CRP values compared to male patients with DMT2. pared to male diabetic patients (p=0.001). The obtained results are in accordance with other studies in which The solid horizontal lines denote the median value, the box rep- influence of gender on serum CRP concentration in type 2 diabetic resents the 25% and 75% inter-quartile ranges and the whiskers rep- patients was assessed (23, 24). Moreover, in our study significant resent minimum and maximum values. increase in serum CRP levels was observed in female compared to CG male – male subjects of the control group (n=30) male healthy control subjects. CG female – female subjects of the control group (n=30) Observed CRP increase in female compared to male patients DMT2 male – male patients with diabetes mellitus type 2 (n=30) with DMT2 might be explained by obesity which is generally more DMT2 female - female patients with diabetes mellitus type 2 frequently seen in women as a result of higher percentage of body (n=30) fat (25). Adipose tissue cells are known to produce among others * - compared to male subjects of the control group pro-inflammatory adipokines such as Interleukin-6 and Tumor Ne- ** - compared to male patients with diabetes mellitus type 2 crosis Factor-alpha which are the most potent stimulators of hepat- p - probability ic CRP synthesis. Novel findings suggest that adipose tissue is the key regulator of serum CRP concentration. Accumulation of body DISCUSSION fat leads to increased production of adipose pro-inflammatory cy- tokines which in turn leads to increased serum CRP concentration Few studies have so far investigated influence of gender on se- (26). Furthermore, possible interaction between sex hormones and rum ADMA concentration. Schulze et al. (2) determined positive inflammation should also not be excluded. correlation between ADMA and age which was influenced by gen- Studies have shown increased cardiovascular disease (CVD) der in healthy subjects. Namely, in this study it was observed that risk in diabetic women compared to diabetic men and available data women up to 50 years of age had lower ADMA values compared point to the conclusion that cardiovascular risk modification and to men of the same age group, while women over 50 had higher treatment is of the at most importance in diabetic patients, especial- ADMA values compared to men of the same age group. Authors ly in women (27). Gender comparison of serum asymmetric dimethylarginine and C-reactive protein concentration in patients with diabetes 89

Based on current evidence cardiovascular risk factors are more 5. Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for C-reactive pro- severe, more common and more likely to cluster in diabetic women tein. Clin Chim Acta. 1981 Nov;117(1):13–23. than in diabetic men. Furthermore, disparities in accessibility, qual- 6. Ishii S, Karlamangla AS, Bote M, Irwin MR, Jacobs DR, Cho HJ, et al. Gender, Obesi- ty and Repeated Elevation of C-Reactive Protein: Data from the CARDIA Cohort. ity and, possibly, effectiveness of care in diabetic women have also PLoS ONE 2012; 7(4):e36062. been documented (28). However, overall reasons for greater aug- 7. Začiragić A, Mulabegović N, Huskić J. Physiological and pathophysiological func- mentation of CVD risk in diabetic women are still not fully under- tions of C-reactive protein and its role in cardiovascular risk assessment: compre- stood. hensive review. Folia Medica 2013;48(1):1-10. We have previously reported increased values of both ADMA 8. Kushner I, Samols D, Magrey M. A unifying biologic explanation for “high-sensitivity” and CRP in patients with DMT2 compared to healthy control sub- C-reactive protein and “low-grade” inflammation. Arthritis Care Res (Hoboken). jects (29, 30). In the attempt to assess the role of endothelial dys- 2010 Apr;62(4):442-6. 9. Packard RRS, Libby P. Inflammation in atherosclerosis: from vascular biology to bio- function and chronic low-grade inflammation as possible culprits for marker discovery and risk prediction. Clin Chem. 2008 Jan;54(1):24-38. reported gender difference in CVD risk we have conducted gender 10. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, comparison of serum ADMA and CRP concentration in patients et al. The vascular endothelium and human diseases. Int J Biol Sci. 2013 Nov 9; with DMT2. Results of the present study have shown elevated 9(10):1057-69. concentration of serum ADMA and CRP in diabetic women com- 11. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascular disease and pared to diabetic men. Both of these compounds are thought to diabetes: a call to action from the American Diabetes Association and the American have significant impact on CVD development and progression, and Heart Association. Circulation. 2006 Jun;113(25):2943-6. 12. Juutilainen A, Kortelainen S, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Gender on diabetes mellitus-associated vascular impairment (31). Obtained difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes results suggest that one of the possible explanations for augmented Care. 2004 Dec;27(12):2898-904. CVD risk in diabetic women might be the observed gender differ- 13. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 ence in an increase of endothelial dysfunction and chronic low-grade diabetes mellitus on ischemic heart disease, stroke, and death: a population-based inflammation markers in DMT2 patients. Due to a small patient sam- study of 13,000 men and women with 20 years of follow-up. Arch Intern Med. 2004 ple of the present investigation, the obtained results require confir- Jul;164(13):1422-6. mation in larger, longitudinal studies. However, if our findings are 14. Kautzky-Willer A, Kamyar MR, Gerhat D, Handisurya A, Stemer G, Hudson S, et al. Sex-specific differences in metabolic control, cardiovascular risk, and interventions to be supported in the future, then gender specific guidelines for in patients with type 2 diabetes mellitus. Gend Med. 2010 Dec;7(6):571-83. CV risk factors detection and correction as well as measures for 15. Vidal-Pérez R, Otero-Raviña F, Grigorian-Shamagian L, Parga-García V, Eirís-Cam- decrease of cardiovascular morbidity and mortality in patients with bre MJ, de Frutos-de Marcos C, et al. Sex does not influence prognosis in diabetic DMT2 should include therapeutic interventions for reduction of se- patients. The Barbanza Diabetes study. Rev Esp Cardiol. 2010 Feb;63(2):170-80. rum ADMA and CRP concentration. 16. Nakhjavani M, Morteza A, Asgarani F, Khalilzadeh O, Ghazizadeh Z, Bathaie SZ, et al. The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes. Gene. 2012 Apr 25;498(1):107-11. CONCLUSION 17. Uslu S, Kebapçi N, Kara M, Bal C. Relationship between adipocytokines and cardio- vascular risk factors in patients with type 2 diabetes mellitus. Exp Ther Med. 2012 The risk of cardiovascular disease in diabetes mellitus type 2 is Jul;4(1):113-120. markedly influenced by gender. Results of the present study have 18. American Diabetes Association. Standards of medical care for patients with diabe- shown higher values of serum ADMA and CRP concentration in tes mellitus (Position Statement). Diabetes Care 1998; 21 (Suppl.1):S23-S31. female compared to male patients with DMT2. Although the mech- 19. Teerlink T, Neele SJ, de Jong S, Netelenbos JC, Stehouwer CD. Oestrogen replace- anisms leading to a greater augmentation of CVD risk in diabetic ment therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clin Sci (Lond). 2003 Jul;105(1):67-71. women remain largely unknown one of the possible explanations 20. Anderssohn M, McLachlan S, Lüneburg N, Robertson C, Schwedhelm E, William- might be more pronounced endothelial dysfunction and low-grade son RM, et al. Genetic and environmental determinants of dimethylarginines and inflammation in diabetic women compared to diabetic men. Longitu- association with cardiovascular disease in patients with type 2 diabetes. Diabetes dinal studies with larger sample size are warranted for confirmation Care. 2014 Mar;37(3):846-54. of the obtained results. 21. Saltevo J, Vanhala M, Kautiainen H, Kumpusalo E, Laakso M. Gender differences in C-reactive protein, interleukin-1 receptor antagonist and adiponectin levels in the metabolic syndrome: a population-based study. Diabet Med. 2008 Jun;25(6):747- Conflict of interest:none declared. 50. 22. Hu G, Jousilahti P, Tuomilehto J, Antikainen R, Sundvall J, Salomaa V. Association of REFERENCES serum C-reactive protein level with sex-specific type 2 diabetes risk: a prospective finnish study. J Clin Endocrinol Metab. 2009 Jun;94(6):2099-105. 1. Caplin B, Leiper J. Endogenous nitric oxide synthase inhibitors in the biology of 23. Saltevo J, Kautiainen H, Vanhala M. Gender differences in adiponectin and low- disease: markers, mediators, and regulators? Arterioscler Thromb Vasc Biol. 2012 grade inflammation among individuals with normal glucose tolerance, prediabetes, Jun;32(6):1343-53. and type 2 diabetes. Gend Med. 2009 Sep;6(3):463-70. 2. Schultze F, Maas R, Freese R, Schwedhelm E, Silberhorn E, Böger R.H. Determina- 24. Qasim AN, Budharaju V, Mehta NN, St Clair C, Farouk S, Braunstein S, et al. Gen- tion of a reference value for NG, NG – dimethyl-L-arginine in 500 subjects. Eur J der differences in the association of C-reactive protein with coronary artery calci- Clin Invest 2005 Oct; 35(10):622-6. um in type-2 diabetes. Clin Endocrinol (Oxf). 2011 Jan;74(1):44-50. 3. Sibal L, Agarwal SC, Home PD, Boger RH. The Role of Asymmetric Dimethylargi- 25. Cartier A, Côté M, Lemieux I, Pérusse L, Tremblay A, Bouchard C, et al. Sex differ- nine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Curr Cardiol ences in inflammatory markers: what is the contribution of visceral adiposity? Am J Rev. 2010 May; 6(2): 82-90. Clin Nutr. 2009 May;89(5):1307-14. 4. Böger RH. Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovas- 26. Wimalawansa SJ. Visceral adiposity and cardiometabolic risks: epidemic of abdom- cular medicine and beyond. Ann Med 2006;38(2):126-36. inal obesity in North America. Res Rep Endocr Disord. 2013;3:17–30. 90 A. Začiragić et al.

27. Roche MM, Wang PP. Sex differences in all-cause and cardiovascular mortality, hos- pitalization for individuals with and without diabetes, and patients with diabetes diagnosed early and late. Diabetes Care. 2013 Sep;36(9):2582-90. 28. Rivellese AA, Riccardi G, Vaccaro O. Cardiovascular risk in women with diabetes. Nutr Metab Cardiovasc Dis. 2010 Jul;20(6):474-80. 29. Začiragić A, Huskić J, Mulabegović N, Avdagić N, Valjevac A, Hasić S, et al. An as- Reprint requests and correspondence: sessment of correlation between serum asymmetric dimethylarginine and glycated Asija Začiragić, MD, PhD haemoglobin in patients with type 2 diabetes mellitus. Bosn J Basic Med Sci. 2014 Department of Human Physiology Feb;14(1):21-4. Faculty of Medicine University of Sarajevo 30. Začiragić A, Huskić J, Hadžović-Džuvo A, Valjevac A, Avdagić N, Mulabegović N. Čekaluša 90 Serum C-reactive protein concentration and measures of adiposity in patients with 71000 Sarajevo type 2 diabetes mellitus. Bosn J Basic Med Sci. 2007 Nov;7(4):322-7. Bosnia and Herzegovina 31. Tousoulis D, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, et Phone: +387 33 226 472 al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers Fax: +387 33 203 670 and therapeutic approaches. J Am Coll Cardiol. 2013 Aug;62(8):667-76. Email: [email protected]

Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Medical Journal (2014) Vol. 20, No. 2, 91 - 95 Original article Comparative analyses of the effect of surgical weakening of inferior oblique muscle overaction on binocularity Komparativna analiza efekta hirurškog slabljenja hiperfunkcije donjeg kosog mišića na binokularni vid

Jasmina Alajbegović–Halimić1*, Denisa Zvizdić1, Haris Tanović2

1Clinic of Ophtalmology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of General and Abdominal Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Inferior oblique overaction (IOOA) can be primary or second- Hiperfunkcija donjeg kosog mišića (IOOA) može biti primarna ili ary, isolated or combined with other types of horizontal deviation, sekundarna, izolovana ili udružena sa drugim vrstama horizontalnog ot- mostly with esotropias (ET). Surgical weakening of inferior oblique klona, najviše sa ezotropijama (ET). Hirurško slabljenja pojačane funk- muscle overaction means several techniques like: recession, myoto- cije donjeg kosog mišića, podrazumijeva nekoliko tehnika kao što su; my, myectomy, anteroposition etc. Goals: we analysed the effect of retropozicija, miotomija, miektomija, anteropozicija itd. Ciljevi: Anali- inferior oblique muscle surgical weakening to binocular vision, com- zirali smo efekat hirurškog slabljenja donjeg kosog mišića na binokularni paring two groups of patients with primary hypertropia. Material vid komparirajući dvije grupe pacijenata koji su imali njegovu pojačanu and methods: in retrospective study, we observed 33 patients who funkciju ili hipertropiju. Materijal i metode: U 5–godišnjoj retrospektiv- were subject to the surgical procedure of weakening inferior muscle noj studiji observirali smo 33 pacijenta kod kojih je rađena hirurška pro- overaction by two methods; recession and myotomy. Results: out cedura slabljenja pojačane funkcije donjeg kosog mišića metodom ret- of 33 patients, 57.6% were male and 42.4% female patients with ropozicije i miotomije. Rezultati: Od 33 pacijenta, bilo je 57.6% muških the average age of 10.6±7.5 (in range of 4–36). There was 33.3% i 42.4% ženskih pacijenata sa prosječnom starosnom dobi od 10.6±7.5 of isolated primary hypertropias, and 66.7% combined with esotro- (u rasponu od 4–36). Izolovanih primarnih hipertropija bilo je 33,3%, a pias. The recession was done in 23 (69.9%) patients and myotomy udruženo sa ezotropijama 66.7%. Kod 23 (69.9%) pacijenta rađena je in 10 (30.1%). Good and stabile binocular vision postoperativly was retropozicija, a kod 10 (30.1%) miotomija. Dobar i stabilan binokular- achieved in 65.2% of patients, on whom the recession of oblique ni vid postoperativno imalo je 65.2% pacijenata kod kojih je rađena muscle was done, which was statistically significant with significance retropozicija donjeg kosog mišića, što je bilo statistički signifikantno level of p<0.05. Conclusion: effect of surgical weakening of the infe- izraženo stepenom vjerovatnoće p<0.05. Zaključak: Efekat slabljenja rior oblique muscle overaction, considering the binocularity, proved pojačane funkcije donjeg kosog mišića, obzirom na binokularni vid, bio better in patients treated with the inferior oblique muscle recession. je bolji kod pacijenata gdje je rađena retropozicija donjeg kosog mišića.

Key words: comparation, weakening, inferor oblique muscle, bin- Ključne riječi: komparacija, slabljenje, donji kosi mišić, binokularni ocularity vid

INTRODUCTION other types of deviations, so more than 50% of patients with hor- isontal strabismus have the vertical deviation too. Primary inferior Hypertropia or eye elevation, in most of the cases is caused by oblique overaction is mainly combined with horizontal deviations, inferior muscle overaction (IOOM). Inferior oblique muscle overac- according to Parks, with congenital esotropias 65% i 35% with inter- tion (IOOA) may be primary or secondary. Primary hyperfunction mitent exotropia. Can be present on one or both eyes simetrically of inferior oblique muscle is characterized by elevation of the eye (1,2,3,4). Surgeries of weakening of inferior oblique muscle are done in adduction, with smaller or minor vertical deviation in the primary because of functional, but the estetic reasons too. The variety of position, with smaller or minor torticolis and negative Bielschowsky surgical procedure have been performed including: recession, hang- test. Secondary hyperfunction of oblique muscle is caused by ipsilat- back recession, myotomy, myectomy, anterior transposition, nasal eral or contralateral paresis of superior oblique muscle, when we, transposition, denervation and muscle fixation. Myotomy is simplier also, have the eye elevation in adduction, but vertical deviation is version of myectomy, not technically complicated and easy to per- present in primary position too, with strong torticolis and positive form; freed oblique muscle is cutted-down, and bonds are freed, Bielschowsky test. Hypertropia can be isolated or combined with after cauterisation. Recession is, according to many authors, the 92 J. Alajbegović–Halimić et al. best method of inferior oblique muscle weakening, and according to RESULTS Parks dominant to all other methods. Isolated muscle is recessed 2 mm laterrally and 3 mm temporally or more towards lateral edge of We analysed a total of 33 patients, of which 19 (57.6%) were insertion of inferior rectus muscle. By this method, recession can be males and 14 (42.4%) females. According to the type of surgery, addopted and dosed in accordance with the hyperfunction degree; we found that number of male patients was higher than female in for 1+ overaction, the inferior oblique muscle is recessed 6 mm; total number and in recession group, while in a myotomy group the for 2+ overaction 10 mm and for 3+ overaction 14 mm, which is number of male and female patients was equal. Statistical analysis the maximum recession (2,3,4). But, the decission on choosing the shows that there is no statistically significant difference of the pa- surgical procedure is individual and based on personal experience tients based on sex distribution, p>0,05 (Table 1). of a surgeon (3). Indications for these surgeries, whether inferior Analysis of average age during the surgery shows that the av- oblique overaction is primary or secondary or associated with the V erage age of the patients subject to surgery was 10.6±7.5 (age pattern, are to treat hypertropia, diplopia, binocular vision compro- 4 to 36), and that the patients in the recession group were old- mise in the field of adduction, torticollis, and to improve cosmetic er, with the average age of 12.4±8.1 (age 5 to 36), compared appearance. However, these surgeriees may have effect not only to patients in myotomy group with average age of 6.5±3.8 on vertical deviation, but also on horizontal deviations in varying (age 4 to 17). Statistical analysis shows the significant differ- degrees (4). When the hyperfunction is unilateral, usualy the only ence in average age during the surgery in accordance to type of one muscle is weakened, and if the hyperfunction is bilateral, weak- surgery presented with significance level of p<0,05 (Table 1). ening procedure is done both-sided. Also, inferior oblique muscle weakening procedure, in case of existence of horizontal deviation, is Table 1 Sex and age of patients according to type of done at the same time with correction of horizontal deviation (3,4). surgery. Sex distribution is not statistically significant (p>0.05), age distribution statistically significant (p<0.05). During and after surgery, more or less regardless of a procedure, Sex / Type of surgery the possible surgery and post-surgery complications must be con- sidered. One of them is intraoperative and postoperative bleeding Type of surgery Total No Recession Myotomy and hemathoma in orbit,” adherent syndroma”, postoperative and Sex Male N 14 5 19 continued hyperfunction of IOM, hypotropia, internal ophthalmo- % 60,9 50,0 57,6 Female N 9 5 14 plegia etc (3,4,5,6,7). % 39,1 50,0 42,4 Total N 23 10 33 MATERIALS AND METHODS % 100,0 100,0 100,0 Age in surgery time / Type of surgery Retrospectivelly, study was performed in the period from Janu- Age N X SD SG Mini Maxi mum mum ary 2007 to December 2013 at the Clinic of Ophtalmology, Clinical Recession 23 12,4348 8,06128 1,68089 5,00 36,00 Center University of Sarajevo. We evaluated a total of 33 patients suffering from primary inferior oblique muscle overaction, isolated Myotomy 10 6,5000 3,80789 1,20416 4,00 17,00 or combined with esotropia. Other forms of horisontal deviations Total 33 10,6364 7,51173 1,30762 4,00 36,00 were not considered. In all patients, the preoperative and postop- erative angle of horizontal esodeviation and vertical deviation was measured, with the prism cover test or Krimsky test, on primary Out of 33 patients, 11 (33.3%) had isolated primary inferior position and 9 diagnostic gaze positions. Binocularity was tested in oblique muscle overaction and 22 (66.7%) patients had it combined accordance with the Lang and Titmus fly tests 3, 6 and 12 months with esodeviation. All patients in the myotomy group had esotropia after the surgery. Patients were divided into two groups: in one (100%). In the recession group, we had almost equal distribution group, depending on vertical deviation, the weakening of inferior of patients with esotropia 12 (52.2%) and hypertropia, only 11 muscle overaction was done by recession and in other by miotomy. (47.8%), which is statistically significant, p=0.007 (Table 2). Horizontal deviation was done at the same time or separatelly with vertical deviation, and depending on the case, it was done by bime- Table 2 Type of deviation based on type of surgical pro- dial recession or combined unilateral recess–resect procedure. The cedure χ2=7.174; p=0.007. data shown in a table are based on the number of cases, percent- Type of deviation/*Type of surgery procedure age, arithmetic mean, standard deviation, median, and rangewere Of the 33 patients, 19 (57,7 %) underwent Type of surgery unilateral weekening procedure and 14 Total presented as descriptive statistics for quantitative data. Qualitative (42,42%) bilateral surgery. Recession Myotomy data are summarized using frequency and percentages. For testing Hyperfunction MOI N 12 10 22 Type of with esotropia % 52,2 100,0 66,7 of predicted hypothesis and prooving the goals, we used the Hi- deviation Only hyperfunction N 11 0 11 square test, Student’s test and Pearson’s or Spearman’s correlation MOI % 47,8 0,0 33,3 N 23 10 coefficient test. Results were accepted as statistically significant on Total value 33 % 100,0 100,0 100,0 the significance level of, p<0,05. Data were analyzed by using statis- tic software IBM Statistics SPSS v21.0 (Chicago, Illinois, USA). The procedures are confirmed with the tenets of the Declaration of Hel- The most commonly performed surgery was inferior oblique sinki. muscle recession, which was done in 23 (69.9%) cases and myoto- Comparative analyses of the effect of surgical weakening of inferior oblique muscle overaction on binocularity 93 my in 10 (30,1%) cases. Out of 33 patients, 19 (57.7%) underwent unilateral weakening procedure and 14 (42.42%) bilateral surgery Table 5 Binocular vision based on a type of surgery 2=5,705; p=0,021. (Table 2). χ Average value of preoperative angle of esodeviation was Type of deviation/*Type of surgery procedure 16.3±9.8 (range 0-35). Those values were more statistically signifi- Of the 33 patients, 19 (57,7 %) underwent Type of surgery unilateral weekening procedure and 14 Total cant in the myotomy group (22.4±5.3; range 14-30), as compared (42,42%) bilateral surgery. Recession Myotomy Hyperfunction MOI N 12 10 22 to the patients in the recession group, presented on significance level Type of with esotropia % 52,2 100,0 66,7 deviation of, p<0.05. Postoperative angle of esodeviation was much smaller Only hyperfunction N 11 0 11 in total number of patients and, on average, it was 3.2±3.8 (range MOI % 47,8 0,0 33,3 N 23 10 Total value 33 -6 to 13), and still higher in the myotomy group (4.5±3.3; range -2 % 100,0 100,0 100,0 to 10), compared to ones in the recession group (2.6±3.9; range -6 to 13), but without statistically significant difference in respect to a In the myotomy group we still had overaction in 2 (6.1%) cases with surgery type, p>0.05 (Table 3). residual angle of vertical deviation. In 1 (4.3%) case in the recession group, we had postoperative hypotropy, and we believed it to be Table 3 Preoperative and postoperative horisontal an- “adhesive syndroma”. Statistical analysis shows that there is no sig- gle of deviations t=6.508; p=0.016. nificant difference in a number of re-operations, in respect to a type of surgery, p>0.05. Type of deviation/*Type of surgery procedure N X SD SG Minimum Maximum Analysis of correlation between binocular vision and other an- alysed parameters showed that, beside statistically significant cor- Recession 23 13,6957 10,15084 2,11660 ,00 35,00 relation, the following factors have the strongest effect on binocular Myotomy 10 22,4000 5,25357 1,66132 17,00 30,00 Total 23 16,3333 9,75214 1,69763 ,00 35,00 vision: older age of patients undergoing surgery (r=0.734), lower Postoperative angle of Esodeviation value of preoperative esotropia deviation angle (r=-0.568), isolat- N X SD SG Minimum Maximum ed hyperfunction of IOM (r=0.429), recession as a type of surgery

Recession 23 2,6087 3,92821 ,81909 -6,00 13,00 procedure (r=-0.416), and smaller postoperative vertical deviation Myotomy 10 4,5000 3,27448 1,03548 -2,00 10,00 angle (r=-0.39). Other parameters did not show any statistically im- Total 33 3,1818 3,79518 ,66066 -6,00 13,00 portant influences (Table 6).

Preoperative angle of vertical deviation in a total number of pa- Table 6 Correlation coefficient towards binocular vision. tients was, on average, 7.5±3.9 (range 3-20) and it was higher in the Correlation coefficient towards binocular vision recession group (8.7±4.3; range 3-20), compared to patients in the Stereovision myotomy group (5.9±2.7; range 4-13), but without statistically sig- * Type of surgery ro -,416 nificant difference in respect to a type of surgery, p>0.05. After the p ,016 surgery, vertical deviation angle was smaller, and, on average, it was Sex ro -,149 1.4±0.96 (range 0-4) in the total number of patients, while the val- p ,409 ues at certain types of surgery were 1.5±0.8 (range 0-3) in patients Age in surgery time ro ,734** from the myotomy group, and 1.3±1.0 (range 0-4) with the patients p ,000 in the recession group, but without statistically significant difference, Type of deviations ro ,429* in respect to a type of surgery, p>0.05 (Table 4). p ,013 Esodeviation preoperative ro -,568** p ,001 Table 4 Preoperative and postoperative horisontal an- Esodeviation postoperative ro -,31 4 gle of deviations t=6,508; p=0.016. p ,075 Preoperative vertical angle of deviation Vertical deviation preoperative ro ,240 N X SD SG Minimum Maximum p ,179 Vertical deviation postoperative ro -,390* Recession 23 8,2609 4,25566 ,88737 3,00 20,00 p 0,025 Myotomy 10 5,9000 2,68535 ,84918 4,00 13,00 Reoperation ro -,262 Total 33 7,5455 3,96146 ,68960 3,00 20,00 p ,141 Postoperative angle of Esodeviation N X SD SG Minimum Maximum *. Correlation signifi cant on a level p<0,05 **. Correlation signifi cant on a level p<0,01 Recession 23 1,3043 1,01957 ,21260 ,00 4,00 Myotomy 10 1,5000 ,84984 ,26874 ,00 3,00 Total 33 1,3636 ,96236 ,16753 ,00 4,00 DISCUSSION

Inferior oblique muscle overaction (IOOA) may be primary or Binocular vision was at 65.2% in the recession group, and at 20% secondary and very often combinated with horisontal deviations, of the patients in myotomy group, which is statistically significant mostly with esodeviations. In our cases, we had a total of 33 pa- shown with significance level of p<0.05 (Table 5). tients, of which 33.3% had only inferior oblique overaction, and 94 J. Alajbegović–Halimić et al.

66.7% inferior oblique muscle overaction with esotropias. Analysis 11 recessions and follow-up period of 12 months. All but one pa- of average age of patients in respect to the type of surgery, shows tient had demonstrable binocular single vision. The average preop- that the average age of the patients who underwent the surgery was erative hyperdeviation in contralateral gaze was 26.5 prism dioptres 10.6±7.5 (range 4-36 years of age), which was statistically signifi- in the myectomies and 20 prism dioptres in the recessions. This was cant, presented on significance level of p<0.05. reduced at 12 months postoperatively to 1.75 prism dioptres in the Wilson and Parks found primary overaction of the inferior myectomies and to 3 prism dioptres in the recessions. Both proce- oblique muscle in 72% of patients with congenital esotropia at an dures were largely self-grading, so that the larger the preoperative average age of 3.6 years, 34% of patients with accommodative es- hyperdeviation, the greater the effect of surgery (9). otropia at an average age of 5.2 years, and 32% of patients with Sekeroglu et al. did the qualitative analysis at 76 patienrs, 30 intermittent exotropia, also at an average age of 5.2 years (7). male and 36 female, average age 11(1-49). Out of 76 patients, Weakening surgery for IOOA either primary or secondary in- 54.5% had secondary hyperfunction of IOM, and 45% primary hy- cludes recession, disinsertion, myectomy, tenotomy, myotomy and perfunction of IOM. Three surgery procedures were done: 8.5% anteriorization. The most commonly performed inferior oblique anteriorization, 43.9% tenotomy and 7.6% recession. They did not muscle weakening procedures are inferior oblique myectomy and found any difference between different types of surgery in terms of inferior oblique muscle recession. The surgical decision appears to horisontal deviations correcting effect. Unfortunatelly, there was no be primarily based on individual experience and preference (7,9). data about binoculararity (10). The aim of all these surgeries is to release IOOA and reduce Ehrt et al. had retrospective studys of 234 patients in the age of related vertical deviations. In previous studies, we found the data 2-81, during the period of 9 years, where the quantitative analysis of better usage of recession, as a modern method of weakening of IOM weakening effect by recession, and described reduction of ver- inferior oblique muscle which is usually compared with myectomy tical deviation from 25 degreses to 6. They propose this method as or transposition, and not with myotomy. We did not find enough safe and suitable, but with smaller risk from consecutive hypotropia data on binocularity in any of the studies. Based on our analysis, and limited elevation, which they got in one case (11). according to binocularity, we showed that stereo vision was present Risović et al. in their study had 79, divided into two groups: first in 65.2% of patienats in the recession group, and in 20% of patients as a primary overaction IOM, and other and disociated vertical de- in the myotomy group, which was statistically significant, presented viation. Binocular vision was found in 67% of patients from the first on significance level of, p<0.05. If we analyse correlation between group and 55.6% patients from the second group, but without big stereo vision and other parameters, we can see that, beside statisti- statistically significant difference between the groups (12). cally significant correlation, the following factors have the strongest influence on stereo vision: older age of patients, smaller deviation CONCLUSIONS angle before the surgery, isolated hyperfunction of inferior oblique muscle, type of surgery – recession, and smaller angle of vertical The intention of the present study was not to evaluate effect of deviation postoperativly. Other parameters did not show statisti- weakening of inferior oblique muscle on horisontal deviation, but cally strong influence. The need for repeated surgery occurred in to investigate its effect to condition of binocular vision. In this re- 2 (6.1%) patients out of a total number of patients, when we still gard, the better results were achieved by applying recession as the had overreaction. In 1 (4.3%) case, we had postoperative hypot- method of inferior oblique muscle weakening. Recession is safe and ropy, and we believed it was the so called adhesive syndroma, but effective procedure to eliminate inferior oblique overaction and can statistical analysis showed that there was no significant difference be dosed and adopt to overaction. But, when planning the surgery in repeating the surgeries in respect to type of a surgery, what was of inferior oblique muscle weakening, the knowledge and experi- significance with, p>0.05. ence regarding its influence on horizontal deviation and binocularity Parks found inferior oblique muscle recession to be the most ef- is needed, as well as dosing and possible operative and postopera- fective procedure. He observed a persistent inferior oblique muscle tive complications. overaction in 37% of patients and inferior oblique muscle underac- tion in 8% of patients after an inferior oblique muscle myectomy Conflict of interest: none declared. and 13% incidence of inferior oblique muscle adhesive syndrome when the myectomy was performed at the inferior oblique muscle REFERENCES insertion (2,3,4,5,7). After the surgery, the angle of vertical deviation decreased, 1. Dorn V, Čelić M. Strabizam i nistagmus. Zagreb: Medicinska naklada 2004;153, and was, on average 1.4±0.96 degrees. In myotomy group it was 460-62. 1.5±0.8 (range 0-3), in recession group 1.3±1.0 (range 0-4), but 2. Parks MM. Study of the weakening surgical procedures for eliminating overaction without statistically significant difference in respect to a type of sur- of the inferior oblique. Trans Am Ophthalmol Soc.1971;69:163-87. gical procedure, p>0.05. 3. Parks MM. Atlas of Strabismus Surgery. Philadelphia, Pa: Harper & Row; 1983. Cooper and Sandall found that a measured recession will de- 4. Parks MM. The weakening surgical procedures for eliminating overaction of the crease the hyperdeviation by 6.88 prism dioptries in primary posi- inferior oblique muscle. Am J Ophthalmol. 1972 Jan;73(1):107–22. 5. Parks MM. Causes of the Adhesive Syndrome. Symposium on strabismus. Trans- tion and by 12.3 prism dioptries in the field of action of the overact- actions of the New Orleans Academy of Ophthalmology. The C.V. Mosby Com- ing inferior oblique muscle. They analyzed recession and myotomy pany: St.Louis,1978;269–279. group, but there is no data about binocularity (8). 6. Kenneth W. Wright, M.D., Peter H. Spiegel, M.D., and Lisa S. Thompson, M.D. Shipman and Burke had total of 23 patients, 12 myectomies and Handbook of Pediatric Strabismus and Amblyopia. New York: Springer Science; Comparative analyses of the effect of surgical weakening of inferior oblique muscle overaction on binocularity 95

2006. Am Orthopt J. 2006;56:200-1 12. Risović D, Petrović L, Kosanović–Jaković N, Misailović K, Stanković B, Erić-Marinković 7. Wilson ME, Parks MM. Primary inferior oblique overaction in congenital esotro- J. Binocular vison and vertical strabismus. Vojnosanit Pregl. 2007 Feb;64(2):109-15. pia, accommodative esotropia, and intermittent exotropia. Ophthalmology. 1989 Jul;96(7):950–5; discussion 956-7. 8. Cooper EL, Sandall GS. Recession versus free myotomy at the insertion of the Reprint requests and correspondence: inferior oblique muscle. J Pediatr Ophthalmol 1969; 6: 6–10. Jasmina Alajbegović-Halimić, MD, PhD 9. Shipman T, Burke J. Unilateral inferior oblique muscle myectomy and recession Clinic of Ophtalmology in the treatment of inferior oblique muscle overaction: a longitudinal study. Eye Clinical Center University of Sarajevo (Lond). 2003 Nov;17(9):1013–8. Bolnička 25 10. Taylan Sekeroglu H, Dikmetas O, Sanac AS, Sener EC, Arslan U. Inferior Oblique 71 000 Sarajevo Muscle Weakening: Is it possible to quantify its effect on horisontal deviations? J Bosnia and Herzegovina Ophthalmol. 2012;2012:813085. Phone: + 387 33 297 191 11. Ehrt O, Beki Y, Boergen KP. Effect of inferior oblique recession in strabismus adduc- Fax: + 387 33 663 668 torius. Strabismus. 2002 Jun;10(2):63-8. Email: [email protected]

Bosnia and Herzegovina is high risk region for fatal CVD events! Bosna i Hercegovina pripada visoko rizičnom regionu za fatalne KV ishode!

10 year risk of fatal CVD in high risk regions of Europe Women Men Non-smoker Smoker Age Non-smoker Smoker 180 7 8 9 10 12 13 15 17 19 22 14 16 19 22 26 26 30 35 41 47 160 5 5 6 7 8 9 10 12 13 16 9 11 13 15 16 18 21 25 29 34 65 140 3 3 4 5 6 6 7 8 9 11 6 8 9 11 13 13 15 17 20 24 120 2 2 3 3 4 4 5 5 6 7 4 5 6 7 9 9 10 12 14 17

180 4 4 5 6 7 8 9 10 11 13 9 11 13 15 18 18 21 24 28 33 160 3 3 3 4 5 5 6 7 8 9 6 7 9 10 12 12 14 17 20 24 60 140 2 2 2 3 3 3 4 5 5 6 4 5 6 7 9 8 10 12 14 17 120 1 1 2 2 2 2 3 3 4 4 3 3 4 5 6 6 7 8 10 12

180 2 2 3 3 4 4 5 5 6 7 6 7 8 10 12 12 13 16 19 22 160 1 2 2 2 3 3 3 4 4 5 4 5 6 7 8 8 9 11 13 16 55 SCORE 140 1 1 1 1 2 2 2 2 3 3 3 3 4 5 6 5 6 8 9 11 120 1 1 1 1 1 1 1 2 2 2 2 2 3 3 4 4 4 5 6 8 15% and over 10% - 14% 180 1 1 1 2 2 2 2 3 3 4 4 4 5 6 7 7 8 10 12 14 5% - 9% 160 e (mmHg) 1 1 1 1 1 1 2 2 2 3 2 3 3 4 5 5 6 7 8 10 3% - 4% 50 2% 140 0 1 1 1 1 1 1 1 1 2 2 2 2 3 3 3 4 5 6 7 1% essu r 120 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 3 3 4 5 < 1% 180 0 0 0 0 0 0 0 0 1 1 1 1 1 2 2 2 2 3 3 4 160 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 3 140 0 0 0 0 0 0 0 0 0 0 40 0 1 1 1 1 1 1 1 2 2

Systolic blood p r 120 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 © 2012 ESC www.escardio.org 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 Cholesterol (mmol/L) 150 200 250 300 mg/dL Medical Journal (2014) Vol. 20, No. 2, 96 - 98 Original article Incidence and risk factors of complications after tonsillectomy Učestalost i riziko faktori komplikacija poslije tonzilektomije

Lana Sarajlić1*, Adnan Kapidžić2, Jusuf Šabanović1, Haris Tanović1, Igor Gavrić1, Ismar Rašić1

1Clinic of General and Abdominal Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of Otorhinolaryngology, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Tonsillectomy is one of the most common surgeries and ac- Tonzilektomija spada među najčešće operativne zahvate i counts for about half of all surgical procedures in children. Mortality čini oko polovinu svih hirurških procedura kod djece. Mortalitet i and morbidity after tonsillectomy are usually result of post-opera- morbiditet nakon tonzilektomije su najčešće posljedica postope- tive bleeding. In addition to the bleeding, the most common com- rativnog krvarenja. Pored krvarenja, najčešće komplikacije uklju- plications include infection, pain, nausea and vomiting. Aim of the čuju infekciju, bol, mučninu i povraćanje Cilj studije je definisati study was todefine major complicarions of tonsillectomy and to de- najčešće komplikacije tonzilektomije i utvrditi njihovu učestalost, termine its incidence possible connection between the age, gender, ispitati moguću povezanost dobi, spola, godišnjeg doba u kojem season of operation, ABO blood type and possible complications. se izvodi operacija, ABO krvne grupe i komplikacija poslije ton- Primary and secondary bleeding were observed as major complica- zilektomije. Od komplikacija su zapažena primarna i sekundarna tions; primary bleeding occurred in 2% of both group subjects, and krvarenja. Primarna su se javila u 2% ispitanika obje skupine, a secondary hemorrhage in 2% of patients from the studied and 4% sekundarno krvarenje u 2% ispitanika ispitivane i 4% ispitanika of the control group patients. The largest number of complications kontrolne skupine. Najveći broj komplikacija je uočen kod starije was observed in the older age respondent groups (23-30 years), dobne skupine ispitanika (23-30 godina) te u ljetnom periodu. and during the summer. There was no statistically significant associa- Nije bilo statistički značajne povezanosti između pojave kompli- tion between the occurrence of complications and the respondents kacija i pola ispitanika. Od ukupnog broja postoperativnih krva- gender. Of the total number of postoperative bleeding the largest renja najveći broj je bio kod ispitanika sa O krvnom grupom, a po number was registered in O blood group patients, while one bleed- jedno krvarenje je bilo kod ispitanika A i B krvne grupe. Razlika je ing in patient with A and B blood group respectively. The difference bila statistički značajna. was statistically significant.

Key words: tonsillectomy, risk factors, complications Ključne riječi: tonzilektomija, riziko faktori, komplikacije

INTRODUCTION foreign body such as an extractes tooth gauze, or tonsillar tissue, cervical vertebral complications such as Grisel ‘s syndrome, retro- Tonsillectomy is one of the most common surgeries and ac- pharyngeal abscess, amputation of uvula, pseudoaneurism of lingual counts for about half of all surgical procedures in children (1). arteries, necrotizing fasciitis and death. The most common serious Mortality and morbidity after tonsillectomy are usually result of complication of tonsillectomy is delayed hemorrhage that occurs in post-operative bleeding. In addition to the bleeding, the most com- 2-4% of patients after surgery (3, 4). Generally it can be expected mon complications include infection, pain, nausea and vomiting (2). that some patients need to be re-admitted to the hospital bacause Complications of tonsillectomy also include; pain, bleeding, respira- of pain control and treating dehydration in cases of decreased oral tory obstruction, pulmonary edema, uvulo-pharyngeal insufficiency, fluid intake due to post-operative pain (5). nasopharyngeal stenosis, pulmonary abscess, Horner’s syndrome, The aim of this article is; 1. to define major complications of optic neuritis, meningitis, septicemia, cerebral abscess, palsy of tonsillectomy and to determine its incidence; 2. to determine pos- glosofaringealnog nerve, recurrent laryngeal nerve palsy, salivatory sible connection between age, gender and season of operation and fistul from the submaxillary glands, mediastinitis, subcutaneous em- possible complications; 3. to determine possible connection be- physema, pulmonary emphysema, Eagle syndrome, aspiration of a tween ABO-blood type and bleeding after tonsillectomy. Incidence and risk factors of complications after tonsillectomy 97

MATERIALS AND METHODS and 50% of studied group subjects. Chi-square test showed that there was no statistically significant difference in the age structure of 100 patients was included in the study that was designed as a the respondents between the two groups, χ2=2.28;p=0.131. prospective cohort study. By analyzing the frequency of complications in relation to the Inclusion criteria; age group it was found that majority of complications occurred in - patients after tonsillectomy, patients aged 23-30 years, 2 in the control and 2 in the study group. - age between 7 and 30, There was statistically significant difference in the incidence of com- - both gender. plications in relation to age groups, χ2=9012; p=0029. Exclusion criteria; There was no statistically significant difference in the incidence of - failure to follow the research plan, complications in relation to gender, p=0.477. There was statistically - irregular control, significant difference in the incidence of complications in relation to the - serious side effects. season in which the operation was performed, and majority of com- plications occurred in summer, p<0.05 (Figure 1, Figure 2, Table 1). RESULTS

In the study group there were 23 (46%) male and 27 female (54%) subjects. Of the total number of subjects in the control group 21 (42%) were male and 29 (58%) were female. Chi-square test showed that there was no statistically significant difference in the gender structure of respondents between the groups; χ2=0.161; p=0.420. Analysis of the age structure of the respondents in this research showed that the middle age of the control group was 14:30 ± 7.71 years, while the middle age of the tested subjects was 16:14 ± 7.81 years. Anova test showed that there was no statistically sig- nificant difference in the age structure of respondents between the examined groups, F=1.404 ; p=0.239. Subjects were divided into three age groups; 7-14 years, 15-22 years and 23-30 years. Figure 2 Of the total number of postoperative bleeding (n=5), the majority occurred in patients with O blood The largest number of respondents from both groups belonged group (n=3), and in one patient with A and one with B to the 7-14 age group, specifically 64% of the control group subjects blood group. The difference was statistically significant.

DISCUSSION

In the 2007 International Journal of Otolaryngology, Fioer- entino et al. published a retrospective study that included 1464 patients, which aim was to investigate the prevalence of post-ton- sillectomy bleeding. Results showed that the secondary bleeding occurred in 41 (2.8%) patients. Majority; 20 (70.7%) did not re- quire active treatment and the remaining 12 (29.2%) required a further surgical treatment to achieve adequate hemostasis. In 4.9% patients bleeding was highly abundant and required transfusion (6). Collison et al. (2000) published a study in ENT Journal, which Figure 1 The highest percentage of respondents from both groups was without complications. Among compli- included 430 patients and studied the incidence and risk factors of cations primary bleeding occurred in 2% of the subjects tonsillectomy. The incidence of bleeding was 4%. Variables asso- from both groups, and secondary bleeding occurred in 2% ciated with bleeding were: the season in which operations were of the tested patients and in 4% of the control group pa- performed (most bleeding was observed in the late spring and tients. summer), age, length of execution procedures (over 35 minutes), estimated blood loss during surgery, and the use of steroids. The Table 1 The relative risk of possible complications was 1.5 times higher in the control as compared to the expe- variables that were investigated, and were not statistically associ- rimental group. ated with bleeding, were gender, indication for surgery, concur- rent illness, personal and familial history of bleeding, preoperative Relative risk 1,5000 coagulation profile, length of stay in hospital and the size of the 95% CI 0,2561 to 8,7854 tonsils (7). z statistic 0,450 In the 2010 International Journal of Paediatric Otorhinolaryn- Significance level P = 0,030 gology, Leonard et al. published a study with 303 patients, and NNT (Benefit) 100,000 investigated the association of ABO blood group and bleeding 95% CI 30,072 (Harm) to ∞ to 18,778 (Benefit) after tonsillectomy. Researchers have tried to demonstrate that 98 L. Sarajlić et al. patients with 0 blood group have several problems associated with 2. Kim MK, Lee JW, Kim MG, Ha SY, Lee JS, Yeo SG. Analysis of prognostic factors thrombosis and may be more prone to bleeding. That blood type for postoperative bleeding after tonsillectomy. Eur Arch Otorhinolaryngol. 2012 indicates the reduction of the expression of Von Willebrand factor Mar;269(3):977-81. 3. Krishna P, Le D. Post-tonsillectomy bleeding: a meta-analysis. Laryngoscope. 2001 of coagulation. Results of the study showed that 63% of respon- Aug;111(8):1358-61. dents in whom the secondary bleeiding occurred were 0 blood 4. Shinhar S, Scotch BM, Belenky W, Madgy D, Haupert M. Harmonic scaplpel ton- group. Although the study could not prove causality, the results sillectomy versus hot electrocautery and cold dissection; an objective comparision. showed that patients with this blood group are prone to second- Ear Nose Throat J. 2004 Oct;83(10):712-5. ary bleeding after tonsillectomy in comparision to the patients of 5. Gallagher TQ, Wilcox L, Mcguire E, Derkay CS. Analyzing factors associated with other blood groups (8). major complications after adenotonsillectomy in 4776 patients: Comparing three tonsillectomy techniques. Otolaryngolo Head and Neck Surg. 2010 Jun;142(6):886- 92. CONCLUSION 6. Schrock A, Send T, Heukamp L, Gerstner A, Botz F, Jakob M. The role of histology and other risk factors for post-tonsillectomy haemorrhage. Eur Arch Otorhinolar- Primary and secondary bleeding were observed as major com- yngol. 2009 Dec;266(12):1983-7. plications; primary occurred in 2% of both group patients, and sec- 7. Leonard D, Fenton J, Hone, S. ABO blood type as a risk factor for secondary post-tonsillectomy haemorrhage. Int J Pediatr Otorhinolaryngol. 2010 Jul;74(7):729- ondary hemorrhage in 2% of the studied and in 4% of the control 32. group patients. The highest number of complications was observed in the older age group of respondents (23-30 years), and during the summer. There was no statistically significant association between the occurrence of complications and gender of the respondents. Of the total number of postoperative bleeding the largest number was registered in patients with O blood group, and one bleeding in patient with A and B blood group respectively. The difference was statistically significant. Reprint requests and correspondence: Lana Sarajlić, MD Conflict of interest:none declared. Clinic of General and Abdominal Surgery Clinical Center University of Sarajevo REFERENCES Bolnička 25 71000 Sarajevo 1. Rivas Lacarte M. Tonsillectomy as a major outpatient procedure. Prospective 8-year Bosnia and Herzegovina study: indications and complications. Comparison with inpatients. Acta. Otorrino- Phone: +387 61 262 330 laringol. Esp. 2000 Apr;51(3):221-7. Email: [email protected]

Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Medical Journal (2014) Vol. 20, No. 2, 99 -101 Original article Efficiency of conservative treatment of postpartum hemorrhages caused by uterine atony Efikasnost konzervativnog tretmana postpartalne hemoragije uslijed atonije uterusa

Mohamad Abou El-Ardat*, Zulfo Godinjak, Nermin Hadžić, Naima Imširija, Aida Dizdarević, Eldar Mehmedbašić, Armina Rovčanin

Clinic of Gynecology and Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 80, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Uterine atony leads to heavy blood loss caused by lack of uter- Atonija uterusa dovodi do pretjerana gubitka krvi zbog neodgo- ine muscle contraction after placenta expulsion. Around 80% of varajuće kontrakcije uterusa nakon rađanja posteljice. Oko 80% žena women with postpartum hemorrhage have some of the risk fac- s postpartalnom hemoragijom ima neki od rizičnih faktora: prera- tors: over-distended uterus due to multiple pregnancy, fetal mac- stegnutost uterusa uzrokovana višeplodnom trudnocom, fetalnom rosomia, polyhidramnios or protracted labor. Active management makrosomijom, polihidramnijon ili protrahiranim porođajem. Aktiv- of the third stage of labor can reduce hemorrhages. Oxytocics are no vođenje treceg porođajnog doba može smanjiti gubitak krvi. Ru- routinely administered intravenously as they are associated with the tinski se daje oksitocin intravenski kao sredstvo prvog izbora zbog minimal side effects. Other conservative methods include manu- malog broja nuspojava. Ostale konzervativne metode su manualna al uterine compression for at least 15 minutes, bladder catheter- uterina kompresija barem 15 minuta, pražnjenje mokracnog mjehura izing, and administration of methylergometrine, misoprostol, or kateterom, a mogu se dati i metilergometrin, misoprostol ili 15-me- 15-methyl Prostaglandin F2α. Research objective was to analyze the til-prostaglandin F2-α. Cilj istraživanja je bio analizirati efekte konzer- effects of conservative treatments and the success rate of medica- vativnog tretmana i uspješnost medikamentozne terapije u tretma- mentous treatment of postpartum hemorrhage caused by uterine nu postpartalne hemoragije uzrokovana atonijom uterusa. Kliničko atony. Cross-sectional prospective – retrospective study included deskriptivna prospetkivno-retrospektivna studija je obuhvatila 30 30 respondents, who gave birth at the Clinic of Obstetrics Clinical ispitanica koje su se porodile na Akušerskoj klinici Kliničkog centra Center University of Sarajevo. All respondents have been diagnosed Univerziteta u Sarajevu. Istraživanje je obuhvatilo 30 ispitanica kod with uterine atony. Depending on the therapy administered (intra- kojih je postavljena dijagnoza atonije uterusa. U odnosu na primje- venous ergometrine, intramuscular prostine 15-M and intravaginal njenu terapiju intravenskog ergometrina, intramuskularnog prostina misoprostol), the respondents were classified into three test groups. 15-M i intravaginalnog misoprostola, sve ispitanice su podjeljene u tri No difference in parity was detected among the patients, and the ispitivane skupine. Između ispitivanih skupina nije usta-novljena razlika primiparae were the least represented (p=0.401). In patients who u paritetu, te su primipare bila najmanje zastupljenije (p=0.401). Kod had ergometrine administered, the bleeding stopped in 40% of the ispitanica kod kojih je apliciran ergometrin u 40% slučajeva došlo je do cases. Prostine 15-M showed a success rate of 60%, whereas the prestanka krvarenja, taj procenat kod ispitanica koje su primile prostin patients who received the first dose of misoprostol showed a suc- 15-M iznosio je 60% dok je kod ispitanica koje su primile prvu dozu cess rate of 90%. The patients who had ergometrine administered misoprostola uspješnost je iznosila 90%. Ispitanice kod kojih je aplici- intravenously stopped bleeding within 30 minutes, which is longer ran ergometrin intravenozno, prestale su da krvare nakon 30 min, što than in the two other tested groups (p<0.05). The patients who je statistički značajno duže u odnosu na druge dvije ispitivane skupine used Prostine 15-M stopped bleeding after approximately 21.16 (p<0.05). Ispitanice koje su primile prostin 15-M prestale su da krvare minutes, and the patients who were administered misoprostol vag- nakon prosječno 21.16 min, a ispitanice koje su primile misoprostol inally stopped bleeding within ca 22.44 minutes. The second and intravaginalno prosječno 22.44min. Između druge i treće ispitivane the third group did not show any statistically significant difference skupine nije ustanovljena statistički značajna razlika u dužini trajanja between the bleeding duration periods (p=0.554). Recent clinical, krvarenja (p=0.554). Dosadašnja klinička, literaturna i akušerska isku- written and obstetrics experience suggests using misoprostol as an stva sugeriraju primjenu misoprostola kao uspješan, jednostavam i jef- effective, simple and cheap drug to stop and control PPH. Miso- tin lijek u zaustavljanju i kontrolisanju PPH. Primjenom misoprostola prostol will prevent many urgent primary postpartum hemorrhages prevenira se veliki broj urgentnih primarnih postpartalnih hemoragija caused by uterine atony and reduce the number of maternal deaths. zbog atonije uterusa te kasnije materalni morbiditet i mortalitet.

Key words: uterine atony, postpartum hemorrhage, misoprostol Ključne riječi: atonija uterusa, postpartalna hemoragija, misoprostol 100 M. Abou El-Ardat et al.

INTRODUCTION RESULTS

Uterine atony leads to heavy blood loss caused by lack of uter- The research included 30 patients who satisfied the crite- ine muscle contraction after placenta expulsion. Around 80% of ria. They were separated into three groups. The chi-squared test women with postpartum hemorrhage have some of the risk factors: showed statistical variances in parity of all patients, and that the over-distended uterus due to multiple pregnancy, fetal macrosomia, groups were dominated by multiparae or pluriparae in relation to polyhidramnios or protracted labor (1). Research has shown that primiparae (p=0.025). However, no variance in parity was detected PPH rates depend on several factors, inter alia: blood loss measure- among the patients, and the primiparae were the least represented ments, monitoring during the third stage of labor (use of uteroton- (p=0.401) (Table 1). ics, massage of the uterus, controlled withdrawal of the umbilical cord), obstetrics interventions (episiotomy, childbirth methods). Table 1 Parity overview of patients. The results depend on the characteristics of the population (size of the population, parity, urban/rural environment, etc.). Clinical Groups Total workers usually visually estimate blood losses, but this method can Group I Group II Group III (ergometrine) (Prostine 15-M) (misoprostol) underestimate the postpartum blood loss by 30 to 50% (2). Typical Count 1 1 1 3 symptoms of this condition are continuous or temporary bleeding Primiparae from the (soft) uterus (1). The first step to reduce PPH is to de- % 10.0% 10.0% 10.0% 10.0% Count 7 4 3 14 termine the main cause. Uterine atony is diagnosed by means of Parity Multiparae bimanual palpation, whereas initial treatment includes massage of % 70.0% 40.0% 30.0% 46.7% Count 2 5 6 13 the uterine corpus and administration of intravenous oxytocin. Man- Pluriparae ual compression of the uterus enables doctors to determine the % 20.0% 50.0% 60.0% 43.3% amount of lost blood and the uterine muscle tone. Soft uterus is Count 10 10 10 30 Total usually subject to palpation, whereas the fundus is further away. In % 100.0% 100.0% 100.0% 100.00% case of heavy bleeding, and if the uterus is contracted, vaginal lacer- Χ2=1,832; df=4; p=0.401 X2=7,400; df=2; p =0.025 ations or retained placenta need to be excluded. This can easily be done by performing a vaginal exam using a speculum and ultrasound Table 2 shows the effects of the first dose of drugs administered (to search for placenta residues). Active management of the third in patients with postpartum hemorrhage caused by uterine atony. In stage of labor can reduce hemorrhages. Oxytocics are routinely patients who had ergometrine administered, the bleeding stopped administered intravenously as they are associated with the minimal in 40% of the cases. Prostine 15-M showed a success rate of 60%, side effects. Other conservative methods include manual uterine whereas the patients who received the first dose of misoprostol compression for at least 15 minutes, bladder catheterizing, and showed the success rate of 90%. The Chi-squared test showed a administration of methylergometrine, misoprostol, or 15-methyl statistically significant variance in stopping the hemorrhage com- Prostaglandin F2α. Even though conservative methods are success- pared to the therapy administered, χ2=5.203; df=1; p=0.023 (Table ful in majority of the PPH cases, sometimes hysterectomy cannot be 2). avoided (3). The aim of this article was to analyze the effects of conservative Table 2 Success rate in stopping the hemorrhage treatments and the success rate of medicamentous treatment of depending on the therapy administered. postpartum hemorrhage caused by uterine atony. Groups Total

Group I Group II Group III MATERIALS AND METHODS (ergometrine) (Prostine 15-M) (misoprostol) Count 6 4 1 11 No Cross-sectional prospective-retrospective study included 30 % 60.0% 40.0% 10.0% 36.7% Count 4 6 9 19 respondents, who gave birth at the Clinic of Obstetrics and Gynea- Ye s

cology of the Clinical Center University of Sarajevo. All respondents Bleeding stopped % 40.0% 60.0% 90.0% 63.3% have been diagnosed with uterine atony. Depending on the thera- Count 10 10 10 30 Total py administered (intravenous ergometrine, intramuscular prostine % 100.0% 100.0% 100.0% 100.00%

15-M and intravaginal misoprostol), the respondents were classified χ 2=5,203; df=1; p=0,023 into three test groups. Due to profuse bleeding, each patient was manually examined, after which drugs were administered. In patients who did not respond to the treatment, the therapy was repeated After the drugs were administered, we measured the time need- or other uterotonic administered. Statistical evaluation included all ed for bleeding to stop. The patients whose bleeding stopped after three groups of patients. Basic demographic data are presented in the first dose of drugs were subject to these measurements. The the tables provided herein. We tested the arithmetic mean value (x), patients who had ergometrine administered intravenously stopped the standard deviation value (s), the standard error value (Sx) and bleeding within 30 minutes, which is longer than in the two oth- the median. A chi-squared test (x²-test) was used for all three inde- er tested groups (p<0.05). The patients who used Prostine 15-M pendent samples, and the quantitative results were analyzed using stopped bleeding after approximately 21.16 minutes, and the pa- ANOVA. The significance rate was p<0.05. tients who were administered misoprostol vaginally stopped bleed- Efficiency of conservative treatment of postpartum hemorrhages caused by uterine atony at the clinic for obstetrics 101 ing within ca 22.44 minutes. The second and the third group did CONCLUSION not show any statistically significant difference between the bleeding duration periods (p=0.554) (Table 3). Recent clinical, written and obstetrics experiences suggest using misoprostol as an effective, simple and cheap drug to stop and con- Table 3 Duration of bleeding after therapy. trol PPH. Misoprostol will prevent many urgent primary postpartum

N Mean Std.Dev Std.Error 95% Confidence Interval for Mean Minimum Maximum hemorrhages caused by uterine atony and reduce the number of Lower Bound Upper Bound maternal deaths. Group I 4 30.00 3.16 1.58 24.96 35.03 26.00 33.00 Group II 6 21.16 1.72 0.70 19.35 22.97 19.00 24.00 Conflict of interest:none declared. Group III 9 22.44 2.35 0.78 20.63 24.25 18.00 26.00 REFERENCES DISCUSSION 1. Kainer F, Hasbargen U. Emergencies associated with pregnancy and delivery: peri- partum hemorrhage. DtschArztebl Int. 2008 Sept;105(37):629-38. Postpartum hemorrhage (PPH) is loss of blood estimated to be 2. Sloan NL, Durocher J, Aldrich T, Blum J, Winikoff B. What measured blood loss tells >500 ml after vaginal delivery, or >1000 ml after C-section within 24 us about postpartum bleeding: a systematic review. BJOG. 2010 Jun;117(7):788-800. hours after delivery. Etiologically speaking, it is a lack of the uterine 3. Rahman SS, Myers JE, Gillham JC, Fitzmaurice R, Johnston TA. Post partum hemor- myotamponade (so called “live ligature”), or thrombotamponade in rhage secondary to uterine atony, complicated by platelet storage pool disease and coagulopathies. Early or primary postpartum hemorrhage (PPPH) partial placenta diffusa: a case report. Cases J. 2008 Dec 13;1(1):393. 4. Kainer F, Schiessl B, Kastner R. Geburtshilfliche Notfälle. GeburtshFrauenheilkd Re- occurs within 24 hours after delivery and is caused by uterine atony/ fresher 2003; 28:161–84. hypotony, retained secundines or their fragments (fragments of cot- 5. El-Rafaey H, Rodeck C. Post-partum hemorrhage: definitions, medical and surgical yledon, membrane, or placenta), forms of invasive malplacentation management. A time for change. Br Med Bull. 2003;67:205–17. (placenta accretafocalis, placenta increta, percreta), cervical lacera- 6. Römer TH, Mallmann, Straube W. Pschyrembel Wörterbuch Therapie in Gynäkol- tions, disseminated intravascular coagulopathy (DIC), rupture and ogie und Geburtshilfe. Berlin: W. de Gruyter. 2001;159. uterus inversion (4-6). This study included patients who suffered 7. Hayman RG, Arulkumaran S, Steer PJ. Uterine compression sutures: surgical man- from postpartum hemorrhages due to uterine atony. The findings agement of postpartum hemorrhage. ObstetGynecol 2002 Mar;99(3):502–6. 8. Allam MS, B-Lynch C. The B-Lynch and other uterine compression suture tech- showed that the highest incidence of postpartum hemorrhage oc- niques. Int J Gynaecol Obstet. 2005 Jun;89(3):236-41. Epub 2005 Apr 19. curred in multiparae and that in only 10% of primiparae the uterine 9. Akhter C, Begum MR, Kabir Z, Rashid M, Laila TR, Zabeen F. Use of a condom to atony was detected. PPH is obstetric hemorrhage that causes high control massive postpartum hemorrhage. MedGenMed. 2003 Sep 11;5(3):38. number of maternal death. PPH causes death of 125.000 (7) wom- en every year, especially in the developing countries (8, 9). If PPH is timely detected and therapy administered, the recovery rates are Reprint requests and correspondence: higher. However, availability of drugs and work routines of obste- Mohamad Abou El-Ardat, MD tricians are often a decisive factor in solving these problems. Having Clinic of Gynecology and Obstetrics evaluated administration of various drugs, the research showed that Clinical Center University of Sarajevo Patriotske lige 81 the drugs available today have different effects on PPH. Detailed 71000 Sarajevo analysis of conservative methods showed that misoprostol is much Bosnia and Herzegovina more effective in treatment of postpartum hemorrhage than ergo- Phone: +387 33 250 285 metrine and Prostine 15-M. Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 102 - 105 Original article Psychiatric comorbidity among opiate addicts on methadone substitution treatment Psihijatrijski komorbiditet opijatskih ovisnika na metadonskoj supstitucionoj terapiji

Rasema Okić *

Institute for Alcoholism and Substance Abuse of Canton Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: opiate addiction as a chronic, relapsing disorder Uvod: opijatska ovisnost kao kronični, recidivirajući poremećaj, is almost never alone, but in comorbid relation with other mental gotovo nikada nije usamljena, već je u komorbiditetnoj relaciji sa disorders. Therefore, the goal of this study was to verify the pres- drugim mentalnim poremećajima. Stoga je cilj ove studije utvrditi ence of psychiatric comorbidity among opiate addicts in methadone prisustvo psihijatrijskog komorbiditeta kod opijatskih ovisnika koji substitution therapy (MST) and to examine differences in the prev- su u programu metadonske supstitucione terapije (MST), te ispitati alence of mental disorders between the two groups of patients. razlike u zastupljenosti mentalnih poremećaja između dvije ispitivane Material and methods: study included a sample of 100 opiate ad- grupe pacijenata. Materijal i metode: ispitivanje je vršeno na uzorku dicts in the MST at the Centre for Addiction Diseases in Zenica, od 100 opijatskih ovisnika na MST u Centru za bolesti ovisnosti u from June to December 2011. Respondents were divided into two Zenici, od juna do decembra 2011 godine. Ispitanici su podijeljeni groups: G1 (50 respondents): stable patients - whose tests for psy- u dvije grup: G1(50 ispitanika): stabilni pacijenti - na testovima na choactive substance - PAS in urine were negative for the past six psihoaktivne supstance-PAS u urinu negativni zadnjih šest i više months or more and G2 (50 respondents): unstable patients on mjeseci i G2 (50 ispitanika): nestabilni pacijenti na testovima na PAS tests of PAS positive urine six or more months in the therapeutic u urinu pozitivni šest i više mjesec u terapijskom procesu. Među process. The respondents of both sexes, at the age between 20-47, ispitanicima su zastupljena oba spola, starosna dob je od 20 do 47 were included in the substitution program for the period from godina, a u programu supstitucije su od jedne do pet godina. Dnevne one to five years. Daily doses of methadone ranged from 5 to 100 doze metadona koje su od 5 mg do 100 mg. Korišteni instrumenti mg. The instruments used in the study were Pompidou forms of u istraživanju su Pompidou obrazac liječenih ovisnika sa osnovnim treated addicts with basic information about the respondents and podacima o ispitaniku i MINI – Međunarodni psihijatrijski intervju za MINI - International psychiatric interview for the major psychiat- glavne psihijatrijske poremećaje iz Osi I DSM-IV i ICD-10. Rezultati: ric disorders at Axis I of the DSM-IV and ICD-10. Results: in both u obje ispitivane skupine našli smo visoku zastupljenost psihičkih groups we found a high prevalence of mental disorders, particular- poremećaja, osobito antisocijalni poremećaj ličnosti, 85% među ly antisocial personality disorder, 85% among unstable patients and nestabilnim pacijentima, odnosno 72% među stabilnim pacientima. 72% among stable patients. Other psychiatric disorders were also I drugi psihički poremećaji su zastupljeni u obje grupe ispitanika: present in both groups of patients: hypomanic and manic episodes, hipomanične i manične epizode, poremećaj panike, anksioznost, panic disorder, anxiety, depressive disorder and OCD. Analysis of depresivni poremećaji i OCD. U ukupnom skoru na MINI testu the MINI test total score showed a significant difference between analiza pokazuje signifikantnu razliku između dvije ispitivane grupe the two groups with p=0.0043 (p<0.05), but not on the individu- sa p=0,0043 (p<0.05), ali ne i na pojedinim subskalama, gdje je al subscales, where p> 0.05. Conclusion: psychiatric comorbidity is p>0.05. Zaključak: psihijatrijski komorbiditet je vrlo zastupljen kod frequent among opiate addicts, regardless of the current therapeutic opijatskih ovisnika, bez obzira na trenutni terapijski odgovor koji oni response they show. Comorbidity represents an aggravating factor daju. Komorbiditet predstavlja otežavajuću okolnost u terapijskom in the therapeutic process and requires a comprehensive, long-term procesu i zahtijeva sveobuhvatnu, dugoročnu psihijatrijsku skrb, na psychiatric care, on the path to long-term stabilization of addicts. putu ka dugoročnoj stabilizaciji ovisnika.

Keywords: psychiatric comorbidity, opiate addiction, methadone Ključne riječi: psihijatrijski komorbiditet, opijatska ovisnost, therapy metadonska terapija

INTRODUCTION 50% of patients addicted to drugs and alcohol also have some other psychiatric disorders (1,2,3). Majority of these are personality disor- Psychiatric comorbidity or dual diagnosis among heroin addicts ders, anxiety and depressive disorder (1,2). According to the studies have been the subject of numerous studies and indicate significant carried out by Leshner, Volkow and Brook it was found that the dual presence of these disorders among them. diagnosis among opiate addicts was present in 30% - 60% of cas- Several large epidemiological studies indicate that approximately es (4,5,6). Some other authors mentions mood disorder, antisocial Psychiatric comorbidity among opiate addicts on methadone substitution treatment 103 behavior and anxiety disorders as often present in heroin addicts, RESULTS which has an impact on their therapeutic outcome (7). When assessing the patient and its mental status it is important Of the total number of respondents (100) 57% used heroin intra- to identify short-term and long-term opiate effects and withdrawal venously, 28% by “sniffing”, and 15% in “other” manner (Figure 1). symptoms that may resemble symptoms of other mental disorders (3). Such cases require special attention in terms of differential di- agnosis, when it is necessary to discern the primary disorder among addiction, intoxication or objective development of endogenous psychoses. Acute mood changes, primarily anxiety and depressive disorders occur during opiate withdrawal (8). Patients in the methadone substitution treatment (MST), with psychiatric comorbidity have a significantly higher risk of frequent hospitalizations caused by additional drug use, than patients without comorbidity, but they receive lower doses of methadone for safety Figure 1 Manner of heroin use. reasons. Increasing doses of methadone among these patients car- ries high risks of overdose and/or lethal outcome. Gender structure indicates that 92 respondents (92%) were In patients who are at higher doses of methadone Axis l comor- males and eight (8%) females. The mean age in the stable patients bidity is less present than in patients at lower doses of methadone group (G1) was 31.59±7.9 and in the unstable (G2) 31.74±7.3 (9). The presence of dual diagnosis and severity of psychopathology years. The mean daily dose of methadone in group of stable (G1) are closely related to therapeutic outcome in terms of further drug patients was 46.5±25.2 and in the unstable addicts (G2) it was use, family and social problems and their employment status (10). 40.48±17.68 (Table 1).

MATERIALS AND METHODS Table 1 Differential characteristics of the tested groups G1 and G2 (age, sex, dose of methadone).

Respondents in the survey are long term heroin addicts on meth- G1 (N=50) G2 (N=50) p adone substitution therapy (MST) at the Centre for Addiction Treat- Age 31.59±7.9 31.74±7.3 t=0.0986 0.9217 ment in Zenica, treated from June to December 2011. The sample Gender Male 47 (94%) 45 (90%) chi=0.136 0.7124 included 100 patients, divided into two groups: G1-stable patients in Female 3 (6%) 5 (10%) substitution (at screening urine tests negative for opiate substances) Mean methadone dose 46.5± 25.19 40.48± 17.68 t=1.3832 0.1698 and G2-unstable patients in the therapeutic process (at screening urine tests positive for opiate substances) in a period of sixth months and The results obtained from the MINI test were interpreted as the more. The source of data was medical documentation (individual pa- sum of answers on all items where the lower limit was 190 points, tient file with daily doses of methadone and the results of screening according to which there was no psychopathological deviations. tests) and International Pompidou form for treated addicts. The pa- However, score above 190 indicates the presence of one or more tients of both sexes, at the age between 20-47 were included in the psychiatric disorders. Therefore, the table shows that the mean of MST program for the period from one to five years. Daily dose of the stable patients was 222.90±20.15 and in the unstable group it methadone in the sample ranged from 5 to 100 mg. was 235.92±24.15, which indicated to a possible presence of one or Exclusion criteria related to: voluntarily interruption of treatment more psychiatric disorders in both groups (Table 2). by the patient, imprisonment, change in the therapeutic direction (de- toxification, joining Therapeutic Community) or changing substituent. Table 2 Mean score of the MINI test in groups of stable The instruments used in the study are: treated addicts form, which and unstable patients. represents the “identity card” of the patient, with personal data, some N Mean Std. deviation Std. Min. Max. Error of mean of which were used in this study (age, gender, level of education), and MINI - International Neuropsychiatric Interview. It is designed as a G1 50 222.90 20.15 2.85 191 269 compact structured interview for the major Axis I psychiatric disorders MINI test G2 50 235.92 24.15 3.35 203 310 from the DSM-IV and ICD-10 classifications. It is a short structured Total 100 229.54 23.11 2.29 191 310 scale based on which it is possible to diagnose psychiatric disorders according to the DSM-IV and ICD -10 for multicenter clinical and epi- demiological studies. The instrument is divided into modules in accor- Results presented in Table 3 show that: the most represented dance with the observed diagnostic categories. mental disorders in both groups of addicts were antisocial person- Statistical data are presented by the absolute number, relative ality disorder: 72% in the therapeutic stable group of patients and number (percentage), the mean and standard deviation in accor- 85% in the unstable group, followed by hypomanic episodes in 56% dance with the type of data. Statistical evaluation was performed by of stable and 62% of unstable group of patients (36% of respon- Chi-Square and Student’s t test. Test results where p<0.05 or at the dents had hypomanic episodes and in 26% of cases manic episodes confidence level of 95% were considered as statistically significant All were found), panic disorder in 54% of stable and 47% of unstable data were analyzed using SPSS statistical software ver. 14 for Windows. patients, and generalized anxiety disorder in 42% of stable and 50% 104 R. Okić

comprehensive psychiatric care (3). Table 3 Frequency of mental disorders by the MINI test in the groups G1 and G2. In this study we cannot help but raise the question of the suf- ficiency of daily doses of methadone. For example, studies have G1 (N=50) G2 (N=50) G1 (N=50) G2 (N=50) Student's p t shown that methadone in adequate doses provides effects of reliev- MINI test - total score 222.90± 20.151 235.92± 24.150 2,9271 0,0043 ing anxiety, depression and psychotic symptoms. Monotherapy with Depression 13.32± 4.053 14.33± 4.647 13 (28%) 18 (36%) 0,6291 0,5342 Hippomanic episodes 17.74± 3.795 19.08± 4.558 28 (56%) 31 (62%) 1,2197 0,2276 methadone generally is not the only, or sufficient therapeutic agent, Panic disorder 25.44± 7.605 25.40± 7.701 26 (52%) 24 (47%) 0,0185 0,9853 because of the presence of psychopathology that seriously desta- Agoraphobia and social 07.04± 1.603 07.10± 1.902 17 (345) 12 (24%) 0,0919 0,9274 phobias bilizes the patient and affects the treatment outcome. Methadone OCD 06.80± 1.641 07.12± 1.875 10 (20%) 15 (30%) 0,4386 0,665 maintenance with adequate doses definitely leads to a reduction of General anxiety 12.16± 3.661 12.60± 3.599 22 (26%) 25 (38%) 0,4149 0,6802 the physical symptoms and psychological distress (15). Antisocial personality 17.84± 3.893 18.50± 3.269 36 (72%) 42 (85%) 0,4182 0,814 disorder The literature references talks about the average doses of meth- adone in patients with comorbidity in order to achieve stabilization of MST unstable patients. Depressive disorder was observed in 26% from 80 mg up to 150 mg/day, and in case of drug addicts with- of stable and 36% of unstable patients. out comorbidity the optimal dose should be from 49 mg up to 99 The analysis shows that there is a significant difference in to- mg/day (11). In our sample the methadone doses were significantly tal MINI score between the groups with t=2.9271 and p=0.0043 lower in both groups, G1 - 46.5±25.2 and G2 - 40.48±17.6. It is (p<0.05), but without statistically significant difference in the indi- possible that patients under dose is an important factor of instability vidual subscales among the groups with p>0.05. and patient demands for the introduction of additional psychiatric treatment, but also increase of the methadone dose. Medium-high DISCUSSION doses of methadone reduce physical symptoms and psychological problems (15). In this study, we found a high prevalence of dual diagnosis, or Of course, we must emphasize the duration of the addiction psychiatric comorbidity among heroin addicts in MST. Numerous substitution treatment program. Wondering about rapid stabiliza- studies worldwide have shown that more than half of opiate addicts tion and long-term quality abstinence, and insisting on a lower dose (11,1) has a personality disorder (in our study 75%), anxiety and of methadone are the most common mistakes and unrealistic con- depression. Although anxiety and depressive disorders are often as- templations of the patients and their families. sociated, we established a higher frequency of anxiety than depres- sive disorders (stable patients 42% of them with anxiety and 26% CONCLUSION of them with depression, or unstable patients - 50% of them with anxiety and 36% of them were depressed addicts) in both groups. In this study we found a high prevalence of psychiatric disorders Interestingly, a study conducted in northern Italy (1,2) on 1090 pa- among opiate addicts in MST. Statistically significant difference was -no tients showed the presence of dual psychiatric diagnoses in 506 pa- ticed based on the total score of mental disorders (p<0.05) among tients (52.7%). stable and unstable patients, but it did not exist in the case of individual For some psychiatric disorders such as depression the most subscales (p>0.05). This leads us to the conclusion that in/stability of common risk factors are: gender, presence of the diagnosis from the patient in the therapeutic process is variable, and it depends on the DSM-IV Axis I, taking any psychotropic drugs, abuse of benzo- many other factors, such as the daily methadone dose, treatment dura- diazepines and methadone dose above 100 mg/day (12). True, in tion, as well as frequency of hospitalizations, additional psychiatric care, our sample the highest dose of methadone which patients receive but also a range of socio-economic parameters, which can be subject was 100mg, and also the presence of depressive disorders was reg- of the future research. istered in less than 50% of the cases. Prevalence of psychiatric disor- ders was up to ten times higher in patients in MST than in the general Conflict of interest: none declared. population, and 2-3 times higher than among potential addicts who are still experimenting or have harmful substance use but are not REFERENCES included in pharmacotherapy (13). Exploring psychiatric comorbidity among patients on MST Ngo 1. Cacciola JS, Alterman AI, Rutherford MJ, McKay JR, Mulvaney FD. The relationship et al. found a significantly higher risk for frequent hospitalizations in of psychiatric comorbidity to treatment outcomes in methadone maintained pa- patients with comorbidity, than among patients without comorbid- tients. Drug Alcohol Depend. 2001 Feb 1;61(3):271-80. 2. Maremmani I, Zolesi O, Aglietti M, Marini G, Tagliamonte A, Shinderman M, Max- ity (14), which is something that we encounter in our daily work. well S. Methadone dose and retention during treatment of heroin addicts with Axis Patients that also use heroin are treated with lower doses of meth- I psychiatric comorbidity. J Addict Dis. 2000;19(2):29-41. adone, mainly for safety reasons, and the risk of over doses. Thus, 3. Pani PP, Maremmani I, Pacini M, Lamanna F, Maremmani AG, Dell’osso L. Effect the patients in our sample are under dosed in relation to the Euro- of psychiatric severity on the outcome of methadone maintenance treatment. Eur pean average. Axis-I comorbidity is declining among patients with Addict Res. 2011;17(2):80-9. doi: 10.1159/000321465. Epub 2010 Dec 17. higher doses of methadone (9). 4. Leshner AI, Drug abuse and mental disorders: Comorbidity is reality. NIDA NOTES Particular attention should be given to the daily methadone 1999; 14(4): 3-4. 5. Volkow ND (2007) Addiction and co-occurring mental disorders. NIDA NOTES dose and duration of substitution treatment. Panni et al. observed 2007;21(2):2. patients who were in substitution for more than a year and found a 6. Brook DW, Brook JS, Zhang C, Cohen P, Whiteman M. Drug use and the risk significant presence of serious psychiatric disorder, which required a of major depressive disorder, alcohol dependence and substance abuse disorders. Psychiatric comorbidity among opiate addicts on methadone substitution treatment 105

Arch Gen Psychiatry. 2002 Nov;59(11):1039-44. 14. Ngo HT, Tait RJ, Hulse GK. Hospital psychiatric comorbidity and its role in heroin 7. Dyer KR, Methadone maintenance treatment and mood disturbances: Pharmaco- dependence treatment outcomes using naltrexone implant or methadone mainte- logical and psychological implications. Heroin Addict Relat Clin Probl. 2005; 7:(2) nance. J.Psychopharmacol. 2011 Jun;25(6):774-82. 5-10 Feltenstein MW. 15. Giacomuzzi SM, Riemer Y, Kemmler G, Ertl M, Richter R, Rössler H, et al. Subjective 8. Jaffe J H, Jaffe AB. Opioid related disorders. In: Sadock B. J., Sadock V. A. (Eds.): wellbeing and somatic markers in methadone substitution. Evaluation of 61 heroin Comprehensive textbook of psychiatry. Lippincott Williams & Wilkins,2000; 1038- addicts. Fortschr Med Orig. 2001 Nov 29;119(3-4):103-8. 1062. 9. Wedekind D, Jacobs S, Karg I, Luedecke C, Schneider U, Cimander K,. et al. Psy- chiatric comorbidity and additional abuse of drugs in maintenance treatment with L- and D,L-methadone. World J Biol Psychiatry, 2010 Mar;11(2 Pt 2):390-9. doi: 10.3109/15622970802176487. 10. Mason BJ, Kocsis JH, Melia D, Khuri ET, Sweeney J, Wells A, et al. Psychiatric comor- bidity in methadone maintained patients. J Addict Dis.1998;17(3):75-89. 11. Maremmani I, Angelo G.I, Dell Osso L. Dual diagnosis heroin addicts: chronology Reprint requests and correspondence: of illnesses. Presentation Abstracts. The 6th European Association of Addiction Rasema Okić, MD, PhD Therapy, 2009, Ljubljana. Institute for Alcoholism and Substance Abuse of Canton Sarajevo 12. Pani PP, Maremmani I, Trogu E, Gessa GL, Ruiz P, Akiskal HS. Delineating the psy- Bolnička 25 chic structure of substance abuse and addictions: Should anxiety, mood and im- 71000 Sarajevo pulse-control dysregulation be included? J Affect Disord. 2010 May;122(3):185-97. Bosnia and Herzegovina doi: 10.1016/j.jad.2009.06.012. Epub 2009 Jul 7. Phone: +387 61 798 809 13. Callaly T, Trauer T, Munro L, Whelan G. Prevalence of psychiatric disorder in a Fax: +387 33 264 106 methadone maintenance population. Aust N Z J Psychiatry. 2001 Oct;35(5):601-5. Email: [email protected]

Bosnia and Herzegovina versions of Guidelines for Patients! Bosanskohercegovačka verzija Vodiča za pacijente! Medical Journal (2014) Vol. 20, No. 2, 106 - 109 Original article Imbalanced values of highly reactive molecule nitric oxide in schizophrenia Vrijednosti visoko reaktivne molekule nitričkog oksida kod shizofrenije

Amra Memić1*, Abdulah Kučukalić1, Lilijana Oruč1, Jasminko Huskić2

1Clinic of Psychiatry, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Institute of Physiology and Biochemistry, Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

For many years, despite many studies it is not clear whether in- Već duži niz godina, bez obzira na mnoge studije, nije jasno da li creased or reduced level of nitric oxide (NO) has some role in the povećane ili smanjene vrijednosti nitričkog oksida (NO) imaju ulogu path physiology of schizophrenia (Sch). Our goalwas to investigate u patofiziologiji shizofrenije (Sch). Ciljnam je bio istražiti da li je nivo whether the serum levels of NO differ between patients suffering nitričkog oksida u serum u različit između grupe pacijenata koji boluju from schizophrenia and healthy controls, and to determine whether od shizofrenije i kontrolne zdrave skupine i utvrditi da li je nivo NO NO level among patients is in correlation with negative and positive između pacijenata u korelaciji sa negativnim i pozitivnim simptomima symptoms of schizophrenia. The study population consisted of 50 pa- bolesti. U istraživanje je bilo uključeno 50 pacijenata koji su bili tients hospitalized at the Psychiatric Clinic of the Sarajevo University hospitalizirani na Psihijatrijskoj klinici, KCUS, i 50 zdravih kontrola. Clinical Center and 50 healthy controls. The best lifetime diagnostic Doživotno najbolja procjena dijagnoze je dodijeljena prema DSM-IV criteria was done based on DSM-IV criteria for Sch confirmed by kriterijima (SCID I). Koncentracija nitričnog oksida (NO) u serumu - - Structured Clinical Interview (SCID 1). NO concentration in serum određena je konverzijom nitrata (NO 3) u nitrite (NO 2) pomoću - was determined by classic colorimetric Griess reaction. Conversion of elementarnog cinka, a zatim mjerenjem koncentracije NO 2 nitrate into nitrite was done with elementary zinc. Our results showed (µmol/L) kolorimetrijski pomoću pripremljenog Greiss reagensa. that the level of NO, in the group of patients with positive symptoms Naši rezultati su pokazali da je koncentracija nitričkog oksida, kod (36.74±4.41) was statistically significantly higher (p<0.0001), and also grupe pacijenata oboljelih od shizofrenije sa pozitivnim simptomima u that the concentration of NO in the group of patients with negative kliničkoj slici (36.74±4.41), veća i statistički signifikantna (p<0.0001), symptoms (33.62±4.69) was higher than in the control group with a koncentracija NO kod grupe pacijenata sa negativnim simptomima statistically significant differences (p<0.002), while there was no statis- (33.62 ± 4.69) je veća u odnosu na kontrolnu grupu ali bez statistički tically significant difference based on type of the symptoms (p>0.05). značajne razlike (p<0.002). Ovi rezultati sugeriraju da postoji razlika These results suggest that there is a difference in NO synthesis in pa- u nivou NO između grupe pacijenata sa dominacijom pozitivnih u tients with positive and negative forms of schizophrenia. odnosu na negativne simptome bolesti.

Key words: nitric oxide, schizophrenia, positive and negative symptoms Ključne riječi: nitrički oksid, shizofrenija, pozitivni i negativni simptomi

INTRODUCTION ease, manifestation and course of illness (2). The constellation of symptoms is more important rather than a single symptom, because During the last decade and nowadays nitric oxide (NO) is a cen- there is not one symptom, which is present in all patients. In mod- tral topic and in focus of many scientific research papers, as well as ern biological research during the last decade psychopathological the possible role of oxidative stress and free radicals in the patho- symptoms are grouped into two types, often three, which overlap physiology of schizophrenia (Sch)(1), since the etiopathogenesis in the clinical picture (3). NO is one of the most important signal- mechanisms in schizophrenia still remains unknown. Schizophrenia ing molecule involved in many cellular events in the cardiovascular, is a serious mental illness, that is the most specific constellation of immune and nervous systems (4), both in physiological and patho- symptoms that reflect the particular existential context of the indi- logical functions, such as the interesting features that has neuro- vidual while maintaining a consistent core in terms of stable, diag- protective, while the high concentrations of pure NO neurotoxic nostically relevant characteristics. This means that the schizophrenic feature (5,6). First facts about the role of the NO came to light manifestations in terms of content show the richness of individual during demonstration of NMDA (N-methyl D-aspartate) glutamate differences, preserving stable patterns related to the onset of dis- receptor stimulation and noticed the release of a molecule that had Imbalanced values of highly reactive molecule nitric oxide in schizophrenia 107

a similarity to the endothelial-derived relaxation factor (EDRF), and trolled study sample consisted of patients from the Clinic of Psychi- shortly thereafter established that EDRF is identical to the NO (7,8). atry, Clinical Center University of Sarajevo, who were taking stable Activation of N-methyl-D-aspartate (NMDA) receptor leads to an doses of the neuroleptics for at least 8 weeks prior to the involve- increase in intracellular calcium that stimulates the enzyme constitu- ment in the study and who gave their written informed consent to tive nitric oxide synthase (NOS), one of the three iso forms of the participate in the study after a detailed explanation of the study pro- enzyme responsible for the formation of NO, which catalyze the cedures. Fifty patients (N=50) with schizophrenia and fifty (N=50) oxidation of L-arginine to L-citrulline and NO (9). In recent stud- healthy subjects participated in this study. A DSM-IV diagnosis of ies with Nogo-A, a myelin-associated protein, it was possible to schizophrenia (20) was established on the basis of independent clin- demonstrate in patients with schizophrenia more marked increases ical interviews and the patients’ psychopathology was assessed with in nNOS/iNOS activity (but not in their expression) in the right, the Scale for the Assessment of Negative Symptoms and the Scale rather than left hemisphere, that is the disturbed asymmetry in cor- for the Assessment of Positive Symptoms (21). Patients and controls tical N-methyl-D-aspartate (NMDA) receptor-nitric oxide synthase with history of psychiatric and chronic diseases such as diabetes (NOS) pathway, which is reported as dysfunctional in schizophrenia mellitus, hypertension, neurology diseases, inflammatory or gastro- (10). Maia-de-Oliveira et al. (2012) showed significantly higher levels enterohepatology diseases were excluded from the study. Fifteen of NO in patients with schizophrenia in comparison to the control milliliters of venous blood was taken from the patients and controls. group, which is often associated with antipsychotic drugs that af- The concentration of NO in blood was determined by measure- fect the increase of nitric oxide plasma and/orserum level (11). For ment of nitrate and nitrite using colorimetric Greiss reaction (22). many years, despite many studies it is still not clear whether increase The concentration of NO in serum was determined by conversion or deficit of NO has some role in the pathophysiology of schizo- of nitrate (NO¯3) to nitrite (NO¯2) using elemental zinc and then phrenia, and Issy et al. (2013) tried to solve this dilemma with the colorimetric measurement of nitrite (NO¯2) (µmol/L). We took 1 effects of NO/cGMP increase on sensory and motor gating modu- mL of blood, added 8 mg of elemental zinc dissolved in 0.4 mL of lation during dopamine hyperfunction as a possible target for drug deionized water, 0.032 ml 5% CH3COOH (acetic acid) and 2 mL development, and it seems that the amphetamine-disruptive effect deionized water. The sample was mixed for 5 min using vortex at is tied to an increase in NO and not to the increase in cGMP (12). room temperature and centrifuged 2.5 min at 700 rpm. After that Minutolo et al. (2012) found a correlation between PANSS score 1 mL of supernatant and 1 mL of Greiss reagent was mixed for and nitrate levels, but it is unclear whether nitric oxide is related to 10 min in vortex at room temperature. After 10 min of mixing we the severity of schizophrenia, because nitrate levels are also affected measured light absorption (optical density) with spectrophotometer by antipsychotic treatment (13). It is well known that the role of at 546 nm. The concentration of nitrate and nitrite was determined NO is associated with other psychiatric entities such as bipolar af- from a standard curve with known concentrations of NaNO2 (1.56 fective disorder, and more recently with major depressive disorder µmol–100 µmol). Distilled water was uses as a blank test to which (5,14). Akpinar et al. (2013) in their research on patients suffering Griess reagent was added. from major depression indicate that serum levels of NO are elevat- ed and that increased serum levels of NO may be associated with Statistical analysis psychomotor retardation but not with the course or severity of the disease (15). Nakano et al. (2010) indicated to a significant decline Excel and SPSS version 15 for Windows was used for the statis- in levels of nitric oxide in schizophrenic patients compared to the tical analyses of data. Categorical variables were compared using the control group, but prior to treatment with risperidone, after which Chi square test and contingency tables. Where appropriate, correla- increase in the levels of NO was observed, and suggested that nitric tions were used to determine the association between continuous oxide was one of the possible candidates that could be linked to variables and to determine the Pearson correlation coefficient. The the pathophysiology of negative symptoms of schizophrenia (16). hypothesis was tested using the paired Student t test. All results are All the above mentioned authors agree that a potentially new treat- presented in tables and figures by type of variables. ment strategy for alleviating social dysfunction in schizophrenia may be NO synthase inhibition, as Wass et al. (2009) confirmed in their study that a significant clinical facts in the pathophysiology of schizo- RESULTS phrenia and the role of nitric oxide is still unclear (17,18,19). The goal of this study was, primarily to determine whether there was The demographics characteristics of the two groups are shown a difference between the level of nitric oxide in the blood serum in Table 1. Analysis by Chi square test and Student t-test indicate of patients with schizophrenia and in the serum of healthy control that significant difference exist, as expected, in employment status group, and secondly to determine whether there was a difference and education level between the two groups (p<0.05), but not in between the level of NO in the serum of patients with positive psy- respect to gender, mean age and marital status (p>0.05). chotic symptomatology and in the group of patients with negative The serum NO levels in the group of patients with schizo- symptoms, and correlation with the same. phrenia (35.8±3.37) were significantly higher than in the control group(15.545±0.87) (Figure 1). We used the paired t-test to com- MATERIALS AND METHODS pare the difference of serum NO level between sch and control group and we got statistical significance at p=0.000, CI (13.31 to This prospective clinical study and partially descriptive con- 27.29), t (5.863). 108 A. Memić et al.

Table 1 Demographic characteristics. accordance with the results of Nakano et al. (16) when their results are compared with other studies that have different result explained Control Sch t/chi with preparation of blood prior to the Greiss reaction such as sam- Male 18 (36.0%) 15 (30.0%) 2=0.407 Gender ple handling and storage procedures, stability of reaction interme- Female 32 (64.0) 35 (70.0%) p=0.523 diates formation of more than one dye, pH, temperature and with t=1.639 repeated sample freezing and repeated dilution. Age 35.56±10.84 38.4±12.5 p=0.105 The level of nitric oxide was higher in the group of patients with Married 23 (46.0%) 21 (42.0%) the prevalence of positive symptoms of schizophrenia, compared to Marital 2=0.171 Single 24 (48.0%) 26 (52.0%) a group of patients with negative symptoms but without statistically status p=0.918 Divorced 3 (6.0%) 3 (6.0%) significant differences, which is in line with the results of studies of Suzuki et al. (24). In this study it is important to note that the in- Employed 39 (78.0%) 9 (18.0%) 2=38.850 volved patients underwent long-term treatment with antipsychotics Employment Unemployed 11 (22.0%) 29 (58.0%) p=0.0001 inducing NOS2 mRNA in various regions of the brain, so there is Retired 0 (0%) 24 (50.0%) a possibility that antipsychotic treatment increased NOS activity in Elementary 4 (8.0%) 11 (22.0%) the previous research subjects which somewhat justifies the above school 2=15.675 mentioned facts. Along these lines of evidence, Nakaki et al. (25) ar- Education High school 21 (42.0%) 32 (64.0%) gued that excessive NO production may lead to neurodegeneration p=0.001 College 7 (14.0%) 2 (4.0%) and the formation of enduring negative symptoms in the brains of Faculty 18 (36.0%) 5 (10.0%) patients with the deficit form of schizophrenia, which partly explains the negative symptoms of schizophrenia (26). Type II, which former- ly classified schizophrenia as negative, unproductive form, is a form of schin in which there is hyperactivity of the central dopaminergic activity, characterized by negative symptoms (alogia, atimia, anhe- donia, social withdrawal, apathy and abulia) (27). Specifically, there are no clear indicators that fully differentiated positive and nega- tive type of disease (28,29,30,31), especially as different varieties of representation may occur at different stages of the disease. We speculate that the discrepancies reflect the heterogeneous psychotic condition of patients. The disadvantage of this research would also Figure 1 NO serum levels. be a control group of drug free schizophrenic patients, which we have not been able to include, as well as determining the level of Our results showed that the level of nitric oxide, in the group nitric oxide from the group of patients who were on typical rather of patients suffering from schizophrenia with positive symptoms than in the group of patients on atypical antipsychotics. We also (36.74±4.41), was higher and statistically significant (p<0.0001), could not observe the difference in changes of NO level before and and the concentration of NO in the group of patients with negative after the treatment. These results suggest that we could not predict symptoms (33.62±4.69) was greater than in the control group also the response to antipsychotic therapy on serum NO levels. Contro- with statistically significant differences (p<0.002). However, no sta- versial results exist when the question is whether the level of Nitric tistically significant difference or correlation (rho=0.074; p=0.055) oxide is higher or lower in patients with schizophrenia compared was found between patients with positive or negative symptoms to the control group. Taken all together the role of nitric oxide in (Figure 2). schizophrenia might be very complicated.

CONCLUSION

The present study suggests that schizophrenic patients differ from control subjects in levels of NO. We found no significant differ- ences in the group of patients with negative symptoms and control subjects. In addition, our study indicates that there is a significant positive correlation between NO and the group of patients with positive symptoms and the control group. Our preliminary findings Figure 2 NO levels based on type of symptoms. of increased serum NO in patients with Sch indicate its potential role in pathophysiology of this severe psychiatric disorder. Howev- DISCUSSION er, those results are preliminary and have to be confirmed in a larger size sample. Bearing in mind heterogeneity in symptom expression, Serum nitric oxide levels in the group of patients suffering with course and treatment our future study has to be focused on re- schizophrenia were significantly higher than in the healthy controls search of this particular characteristics and NO role in ethiopathol- which is consistent with the results of Necat et al. (23), but not in ogy of Sch. Imbalanced values of highly reactive molecule nitric oxide in schizophrenia 109

Conflict of interest: none declared. 19. Akyol O, Herken H, Uz E, Fadillioğlu E, Unal S, Söğüt S, et al. The indices of endog- enous oxidative and antioxidative processes in plasma from schizophrenic patients: REFERENCES the possible role of oxidant/antioxidant imbalance. ProgNeuropsychopharmacol- Biol Psychiatry 2002 Jun;26(5):995-1005. 20. First MB, Spitzer RL, Gibbon M et al. (1997) DSM-IV Axis I Disorders (SCID-I) 1. Wu JQ, Kosten TR, Zhang XY. Free radicals, antioxidant defense systems, and Clinical Version First published in the United States by American Psychiatric Press, schizophrenia. ProgNeuropsychopharmacolBiol Psychiatry 2013 Oct 1;46:200-6. Inc. Washington DC and London, England. 2. Carpenter WT, Heinrichs DW, Wagman AM. Deficit and non-deficit forms of 21. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) schizophrenia: the concept. Am J Psychiatry. 1988 May;145(5):578-83. for schizophrenia. Schizophr Bull. 1987;13(2):261-76. 3. Shan D, Yates S, Roberts RC, McCullumsmith RE. Update on the neurobiology of 22. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. schizophrenia: a role for extracellular microdomains. Minerva Psichiatr. 2012 Sep Analysis of nitrate, nitrite and [15N]nitratein biological fluids. Anal Biochem. 1982 1;53(3):233-249. Oct;126(1):131-8. 4. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. 23. Yilmaz N, Herken H, Cicek HK, Celik A, Yürekli M, Akyol O. Increased Levels of Trends Neurosci. 1991 Feb;14(2):60-7. Nitric Oxide, Cortisol and Adrenomedullin in Patients with Chronic Schizophrenia. 5. Bernstein HG, Bogerts B, Keilhoff G. The many faces of nitric oxide in schizophre- Med PrincPract. 2007;16(2):137-41. nia. A review. Schizophr Res. 2005 Oct 1;78(1):69-86. 24. Suzuki E1, Nakaki T, Nakamura M, Miyaoka H. Plasma nitrate levels in deficit versus 6. Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, et al. A redox-based non-deficit forms of schizophrenia. J PsychiatryNeurosci. 2003 Jul;28(4):288-92. mechanism for the neuroprotective and neurodestructive effects of nitric oxide and 25. Nakaki T, Mishima A, Fujii T et al. Nitric oxide and neurodegenerative diseases. related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626-32. Curr Top PulmPharmacolToxicol. 1997; 3:157-63. 7. Garthwaite J, Charles S, Chess-Williams R. Endothellium-derivedrelaxing factor re- 26. Buchanan RW1, Strauss ME, Kirkpatrick B, Holstein C, Breier A, Carpenter WT lease on activation of NMDA receptors suggests role as intercellular messenger in Jr. Neuropsychological impairments in deficit vs non deficit forms of schizophrenia. the brain. Nature. 1988 Nov 24;336(6197):385-8. Arch Gen Psychiatry. 1994 Oct;51(10):804-11. 8. Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiol- 27. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A. Assessment of ogy. Free Radic Res. 1999 Dec;31(6):577-96. glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to 9. Calabrese V, Butterfield DA, Scapagnini G, Stella AM, Maines MD. Redox regula- the negative and executive/cognitive symptoms of schizophrenia. Neuropsycho- tion of heat shock protein expression by signaling involving nitric oxide and carbon pharmacology. 2009 May;34(6):1578-89. monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. 28. Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr. The Antioxid Redox Signal 2006 Mar-Apr;8(3-4):444-77. schedule for the deficit syndrome: an instrument for research in schizophrenia. Psy- 10. Krištofiková Z, Vrajová M, Sírová J,Valeš K, Petrásek T, Schönig K, et al. N-Meth- chiatry Res. 1989 Nov;30(2):119-23. yl-d-Aspartate Receptor - Nitric Oxide Synthase Pathway in the Cortex of No- 29. Keefe RS, Lobel DS, Mohs RC, Silverman JM, Harvey PD, Davidson M, et al. Diag- go-A-Deficient Rats in Relation to Brain Laterality and Schizophrenia. Front Be- nostic issues in chronic schizophrenia: Kraepelinian schizophrenia, undifferentiated havNeurosci. 2013 Aug 12;7:90. schizophrenia, and state-independent negative symptoms. Schizophr Res. 1991 11. Maia-de-Oliveira JP, Trzesniak C, Oliveira IR, Kempton MJ, Rezende TM, Iego S, Mar-Apr;4(2):71-9. et al. Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic 30. Keefe RS, Mohs RC, Davidson M, Losonczy MF, Silverman JM, Lesser JC, et al. review and meta-analysis. Rev Bras Psiquiatr. 2012 Oct;34Suppl 2:S149-55. Kraepelinian schizophrenia: a subgroup of schizophrenia? Psychopharmacol Bull. 12. Issy AC, Pedrazzi JF, Yoneyama BH, Del-Bel EA. Critical role of nitric oxide in the 1988;24(1):56-61. modulation of prepulse inhibition in Swiss mice. Psychopharmacology (Berl). 2014 31. Buchanan RW, Strauss ME, Breier A, Kirkpatrick B, Carpenter WT Jr. Attentional Feb;231(4):663-72. impairments in deficit and nondeficit forms of schizophrenia. Am J Psychiatry. 1997 13. Minutolo G, Petralia A, Dipasquale S, Aguglia E. Nitric oxide in patients with schizo- Mar;154(3):363-70. phrenia: the relationship with the severity of illness and the antipsychotic treatment. Expert OpinPharmacother. 2012 Oct;13(14):1989-97. 14. Suzuki E,Yagi G, Nakaki T, Kanba S, Asai M. Elevated plasma nitrate levels in depres- sive states. J Affect Disord. 2001 Mar;63(1-3):221-4. 15. Akpinar A, Yaman GB, Demirdas A,Onal S. Possible role of adrenomedullin and nitric oxide in major depression. ProgNeuropsychopharmacolBiol Psychiatry.2013 Oct 1;46:120-5 16. Nakano Y, Yoshimura R, Nakano H, Ikenouchi-Sugita A, Hori H, Umene-Na- kano W, et al. Association between plasma nitric oxide metabolites levels and Reprint requests and correspondence: negative symptoms of schizophrenia: a pilot study. Hum Psychopharmacol. 2010 Amra Memić, MD, MSc Mar;25(2):139-44. Clinic of Psychiatry 17. Wass C, Klamer D, Fejgin K, Pålsson E. The importance of nitric oxide in social Clinical Center University of Sarajevo dysfunction. Behav Brain Res. 2009 Jun 8;200(1):113-6. Bolnička 25 18. Zoroglu SS, Herken H, Yurekli M, Uz E, Tutkun H, Savaş HA, et al. The possible 71000 Sarajevo pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia. Bosnia and Herzegovina J Psychiatr Res. 2002 Sep-Oct;36(5):309-15. Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 110 - 115 Original article Epidemiological and clinical characteristics of childhood lymphoma Epidemiološke i kliničke karakteristike limfoma dječije dobi

Edo Hasanbegović*, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić

Pediatric Clinic, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: lymphomas are the primary neoplasias of the lym- Uvod: limfomi su primarne neoplazije limfnog sistema koje se phatic system, which are usually manifested by painless enlargement najčešće manifestiraju bezbolnim povećanjem limfnih čvorova. of the lymph nodes.In children, the third most common malignan- Predstavljaju 10-13% novootkrivenih malignoma dječije dobi. cy are lymphomas, after leukemias and brain tumors. They repre- Nakon leukemija i tumora mozga, limfomi se nalaze na trećem sent 10-13% of newfound malignancies in children. There has been mjestu po učestalosti maligniteta dječije dobi. Primjetan je napredak progress in the last 20 years as a diagnostic as well as therapeutic. u zadnjih 20 godina kako dijagnostički, tako i terapijski. Bez obzira Despite the progress of genetics, molecular biology and immunol- što su genetika, molekularna biologija i imunologija napredovali i ogy, and their significant results, causes of these diseases have not dali značajne rezultate, uzroci nastanka ovih oboljenja još uvijek nisu yet been identified. Aim: the aim of this study is to evaluate the utvrđeni. Cilj rada: cilj rada je evaluirati osnovne epidemiološke i basic epidemiological and clinical characteristics of childhood lym- kliničke karakteristike limfoma dječije dobi na Hematoonkološkom phoma at the Hematooncology Department of Pediatric Clinic of odjelu Pedijatrijske klinike Kliničkog centra Univerziteta u Sarajevu the Sarajevo University Clinical Center (CCUS) in a ten year period. u desetogodišnjem periodu. Isptanici i metode: istraživanjem je Patients and methods: the study included 58 patients, of both gen- obuhvaćeno 58 pacijenta, oba spola, u dobi od 0-15 godina, kod kojih der, aged 0 through 15, with diagnosis of lymphoma at the Hema- je dijagnostikovan limfom na Pedijatrijskoj klinici KCUS-u u periodu tooncology Department of the Pediatric Clinic of CCUS, during the od 01.01.2004. do 31.12.2013. Sprovedena je retrospektivna analiza period from January 1st 2004 to December 31st 2013. The retro- oboljelih od limfoma dječije dobi. Dobiveni rezultati su predstavljeni spective study of patients with lymphoma in childhood was con- tabelarno i grafički, brojem i procenatualnom vrijednošću. Fišerovim ducted. The results were presented using tables and charts, with i Hi-kvadrat testom je testirana razlika od normalne distribucije, number of cases and percentages. Statistical analysis of significant a kao statistički značajna razlika smatran je (p<0,05). Rezultati: differences was performed using Fisher and Chi - square test. The Od ukupno 58 pacijenata oboljelih od limfoma dječije dobi, bilo values of p<0.05 or on the level reliability of 95% were considered je 37 (63.80%) dječaka i 21 (36.20%) djevojčica, što pokazuje da statistically significant. Results: our study included 58 patients, 37 dječaci više oboljevaju od djevojčica. Najviše oboljelih bilo je u (63.80%) boys and 21 (36.20%) girls. It showed a higher percentage dobnoj skupini od 8 - 15 godina i to 38 (65,50%). Vodeći simptom prevalence of boys compared to girls. Most patients were in the age limfoma dječije dobi je limfadenopatija, koja je bila prisutna kod 45 group of 8-15 years, 38 (65.50%) patients. The leading symptom (77.58%) pacijenata, zatim subfebrilnost kod 19 (32.75%), blijedilo of lymphoma in childhood was lymphadenopathy, which was pre- kod 16 (27.59%), hepatosplenomegalija kod 13 (22.41%), te gubitak sented in 45 (77.58%) patients, followed by subfebrile temperature tjelesne težine kod 12 (20.69%) pacijenata. Kod 16 pacijenata sa HL in 19 (32.75%), paleness in 16 (27.59%), hepatosplenomegaly in 13 i 14 pacijenata sa NHL, bile su povišene vrijednosti LDH, a Cu u (22.41%), and weight loss in 12 (20.69%) patients. The following serumu kod 15 pacijenata sa HL i 10 pacijenata sa NHL. Najviše elevated values were noted: LDH in 16 patients with HL and 14 pacijenata oboljelih od HL-a je dijagnosticirano u II stadiju bolesti with NHL, and Cu in 15 patients with HL and 10 with NHL. Most i to 12 (37.50%), a u IV stadiju 11 (34.40%) pacijenata. Najviše patients with HL were diagnosed in stage II of disease, 12 (37.50%) pacijenata oboljelih od NHL-a je dijagnosticirano u II stadiju i to 13 patients, and 11 (34.40%) in stage IV. Most patients with NHL were (50%), te u IV stadiju 8 (30.80%). Nakon leukemija (157 pacijenata diagnosed in stage II, 13 (50%), and 8 (30.80%) in the IV stage. Af- – 39.20%), limfomi su na drugom mjestu malignih oboljenja kod ter leukemias (157 patients – 39.20%), lymphomas were the second djece. Predstavljaju 14.50% svih maligniteta dijagnosticiranih na malignancies in children, represented with 14.50% of all malignancies Pedijatrijskoj klinici KCUS-u. Godišnje se prosječno javlja 5.8 diagnosed at the Pediatric Clinic. Each year, an average 5.8 of new novooboljelih, a najviše ih je bilo 2013. godine i to 10 (17.20%). cases has ocurred and majority of them (10 new cases) in 2013. Desetogodišnje preživljavanje oboljelih od HL iznosilo je 87.50%, Ten-year survival of patients with HL was 87.50% and 80.77% with a u slučaju NHL 80.77%. Zaključak: limfomi su na drugom mjestu NHL. Conclusion: lymphomas are the second malignancies in chil- malignih oboljenja kod djece na Pedijatrijskoj klinici KCUS-u. Najviše dren at the Pediatric Clinic of CCUS. Most patients are in the age oboljelih je u dobnoj skupini od 8–15 godina. Više obolijevaju dječaci. group of 8-15 years, with higher percentage prevalence of boys Kliničko – dijagnostičke metode i savremena terapija na Pedijatrijskoj compared to girls. Clinical diagnostic methods and modern therapy klinici doprinose dobroj prognozi za pacijente oboljele od limfoma at the Pediatric Clinic contribute to the good prognosis for patients dječije dobi. Stope preživljavanja naših pacijenata odgovaraju istim u suffering from lymphoma in childhood. The survival rates of pa- svjetskim centrima. tients are similar to those in the international centres. Keywords: Lymphoma, Hodgkin’s, Non Hodgkin’s Ključne riječi: Limfom, Hodgkin, Non Hodgkin Epidemiological and clinical characteristics of childhood lymphoma 111

INTRODUCTION types: B-cell Non-Hodgkin’s lymphoma (Burkitt and non-Burkitt’s lymphoma), diffuse large B-cell lymphoma, lymphoblastic lympho- In the general population, neoplasms in children represent 1% of ma, anaplastic large cell lymphoma. Five-year survival in patients who all malignancies. By cause of death, they are in second place right af- were diagnosed with NHL under twenty years was 86% (6, 7, 8). ter the accidents, with a prevalence of 10.60%. In children, the most The aims of this study was to evaluate the basic epidemiological common neoplasms are: leukemias, brain tumors and lymphomas. and clinical characteristics of childhood lymphoma at the Hema- Lymphomas are the primary neoplasias of the lymphatic system, tooncology Department of the Pediatric Clinic of Sarajevo (CCUS) which are usually manifested by painless enlargement of the lymph over the period of ten years. nodes. They represent 10 - 13% of newfound malignancies in chil- dren. Lymphomas are divided into Hodgkin’s lymphoma (HL) and MATERIALS AND METHODS Non-Hodgkin’s lymphoma (NHL) which are so different diseases in epidemiology, biology, diagnostic approach, treatment and progno- The study included children diagnosed with malignant lymphoma sis, that they are treated quite separately. NHL represent about 60% (Hodgkin’s and Non-Hodgkin’s lymphoma), at the Hematooncolo- of children’s lymphomas (1, 2). gy Department of the Pediatric Clinic of CCUS, during the period Hodgkin’s lymphoma is the most common malignant lympho- from January 1st 2004 to December 31st 2013. Total of 58 patients ma, characterized by hyperplasia fields of lymphoid tissue in which were subject to the analysis, 37 boys and 21 girls, aged 0 - 15 years. there are Reed-Sternberg (RS) cells. It usually starts as a painless The retrospective study of patients with lymphoma in childhood lymphadenopathy, usually in the neck, and later the disease expands was conducted. The data (clinical and laboratory parameters) were to other lymph nodes and may cause infiltration extra - lymphatic collected by studying the medical records of patients, and trial was organs and tissues. Lymph nodes are much bigger and stronger than conducted through a questionnaire. The results were presented us- in benign lymphadenopathy, which is usually seen in children. Gener- ing tables and charts, with number of cases and percentages. Statisti- al symptoms such as fever > 38 ° C, body weight loss > 10% in the cal analysis of significant differences was performed using Fisher and last 6 months, night sweats, itchy skin, also called B symptoms, are Chi square test. The values of p<0.05 or on the level reliability of not so common in children (3). 95% were considered statistically significant. The etiology of the disease is not clear. Most likely, it is import- The following was analyzed: ant influence of genetic predisposition and environmental factors, • gender and age of patients with Hodgkin’s (HL) and Non Hod- of which important socio-economic and infectious factors are im- gkin’s lymphoma (NHL) portant once. In almost 75% of the examples of HL in childhood it is • the ratio of patients with HL and NHL towards other malignant possible to prove the involvement of Epstein-Barr virus. In order to diseases in childhood determine the treatment, the stage of the disease is determined on • distribution of patients with HL and NHL by the year of occur- the basis of diagnostic biopsy and anatomical distribution. Intra-ab- rence dominal disease is normally diagnosed radiologically (ultrasound, • distribution of patients with HL and NHL by the cantons of CT, MRI) (3). FB&H Four types of HL are differentiated histopathologically: lympho- • clinical features of patients cyte predomination, nodular sclerosis, mixed cellularity and lym- • laboratory parameters phocyte depletion. The most favorable prognosis has lymphocyte • histopathologic classification predomination, and the least favorable lymphocyte depletion. Lym- • classification according to the degree of lymphoma spreading. phocyte depletion is rarein children (4, 5). The treatment of HL in the last 40 years has dramatically im- proved. With the combination therapy, which includes chemothera- RESULTS py and radiotherapy, permanent cure is achieved in 80% of patients. The most frequently applied protocols for the treatment of HL in Table 1 shows the gender distribution of children with HL or children are: ABVD (Adryamicin, Bleomycin, Vincristine, DTIC), NHL in ten year period. Malignant lymphoma was diagnosed in 58 ChlVPP (Chlorambucil, Vinblastine, Procarbasid, Pronison), COPP patients, 37 (63.80%) boys and 21 (36.20%) girls. There was a sta- (Ciclofosfamid, Oncovin, Procarbazine, Pronison) (4, 5). tistically significant difference between the groups of boys and girls Non-Hodgkin’s lymphomas (NHL) are clonal malignancies of with NHL (p=0.006; Chi-square=7.538). lymphocytes. NHL are heterogeneous group of lymphoproliferative neoplasms marked by the emergence of malignantly altered lym- Table 1 Gender distribution of children with lymphoma. phocytes in the lymph node, and rarely primary in other organs.It Chi-square is characterized by rapid growth, early dissemination and a high de- Lymphoma Boys Girls Total p-value gree of malignancy. Extremely rare occurs in children under 2 years, test χ2 after which the frequency increases gradually during childhood. The HL 17 15 32 0,724 0,125 peak is reached between 7-10 years. NHL is 2-3 times more fre- % 53,10 46,90 100,00 quent in boys than in girls (6, 7, 8). NHL 20 6 26 0,006 7,538 According to the cell lines it belongs to, Non-Hodgkin’s lym- % 76,90 23,10 100,00 phoma is divided into B-NHL and T-NHL group. The World Health Total 37 21 58 Organization (WHO) has classified NHL in children at four main % 63,80 36,20 100,00 112 E. Hasanbegović et al.

Table 2 Age distribution of children with lymphoma. Table 4 Distribution of patients with HL and NHL by the cantons of FB&H. Age !! !! !! 0 - 1 2 - 7 8 - 15 Chi- square Number and percentage of patients Lymphoma Total p - value Canton years years years test 2 χ HL % NHL % Total % HL 0 9 23 32 0,013 6,125 Una-Sana 3 9,40 4 15,40 7 12,10 % 0 28,10 71,90 100,00 Posavina 0 0,00 0 0,00 0 0,00

NHL 0 11 15 26 0,433 0,615 Tuzla 8 25,00 7 26,90 15 25,90 % 0 42,30 57,70 100,00 8 25,00 2 7,70 10 17,20 Total 0 20 38 58 0,018 5,586 Zenica-Doboj % 0 34,50 65,50 100,00 Bosnian Podrinje 0 0,00 0 0,00 0 0,00 p- value n/a 0,655 0,194 Central Bosnia 4 12,50 2 7,70 6 10,30 Chi- square 0,2 1,684 test χ2 Herzegovina-Neretva 2 6,20 1 3,80 3 5,20 West Herzegovina 0 0,00 0 0,00 0 0,00 Table 2 shows the age distribution of children with malignant Sarajevo 6 18,80 10 38,50 16 27,60 lymphoma. Most of the patients were in the age group of 8 - 15 Canton 10 0 0,00 0 0,00 0 0,00 Brčko District 1 3,10 0 0,00 1 1,70 years, precisely 38 patients (65.50%). There was a statistically sig- Total 32 100,00 26 100,00 58 100,00 nificant difference in the total morbidity of malignant lymphoma between the age group of 2 - 7 years and 8 - 15 years (p=0.018; Chi-square=5.586) and morbidity of HL between the age group of Table 5 Clinical signs and symptoms of patients with malig- 2 - 7 and 8 - 15 years (p=0.013, Chi-square=6.125). nant lymphoma.

Symptomatology HL NHL p-value

Lymphadenopathy 26 19 0,297

Loss of appetite 7 3 0,206

Subfebrile temperature 9 10 0,819 Weakness 4 8 0,248 Hepatosplenomegaly 7 6 0,782 Weight loss 7 5 0,564 Paleness 11 5 0,134 Cough 3 6 0,317 Dryness of the oral mucosa Figure 1 The distribution of malignant diseases in the peri- 2 0 n/a

od 2004 – 2013. Excessive sweating 2 1 0,564

Pain in the abdomen 3 5 0,48

Pain in the bones 1 5 0,102 Figure 1 shows the number of patients with malignant diseases treated at the Pediatric Clinic in a ten year period. The total number of malignancies was 401, of which most were leukemias, 157 pa- Table 5 shows the representation of symptoms in malignant tients (39.20%), followed by lymphomas, in 58 patients (14.50%). lymphoma patients. The most frequent symptoms related to lymph- adenopathy (HL in 26, NHL in 19 patients), subfebrile temperature Table 3 Distribution of patients by the year of occurrence. (HL in 9, NHLin 10 patients), paleness (HL in 11, NHL in 5 patients) and hepatosplenomegaly (HL in7, NHL in 6 patients). There was Year 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Total no statistically significant difference between the number of HL and HL 5 7 6 4 0 1 1 4 0 4 32 (3,20) NHL patients with these symptoms. % 15,60 21,90 18,80 12,50 0,00 3,10 3,10 12,50 0,00 12,50 100,00 NHL 3 2 2 4 1 2 2 2 2 6 26 (2,60) Table 6 Laboratory parameters. % 11,50 7,70 7,70 15,40 3,80 7,70 7,70 7,70 7,70 23,10 100,00 Total 8 9 8 8 1 3 3 6 2 10 58 (5,80) Laboratory parameters HL NHL p-value % 13,80 15,50 13,80 13,80 1,70 5,20 5,20 10,30 3,40 17,20 100,00 LDH 16 14 0,715

Table 3 shows the number of new cases of malignant lymphoma FERRITIN 4 1 0,18 per year in the period 2004 - 2013. Most patients with HL were BETA 2 GLOBULIN 5 4 0,739 registered in 2005, 7 patients (21.90%) and with NHL in 2013, 6 Serum Cu 15 10 0,75 (23.10%) patients. Table 4 shows the number of patients with malignant lymphoma Table 6 shows nonspecific laboratory parameters. In 16 patients by the cantons of the Federation of Bosnia and Herzegovina and with HL and 14 with NHL levels of LDH were elevated, and Cu Brčko District. Sarajevo Canton led with 16 (27.60%) patients, fol- serum levels in 15 patients with HL and 10 with NHL. There was lowed by Tuzla Canton with 15 (25.90%) and Zenica-Doboj Canton no statistically significant difference between laboratory parameters with 10 (17.20%) patients. and the type of lymphoma. Epidemiological and clinical characteristics of childhood lymphoma 113

p=0.152, p > 0.05 p=0.01, p< 0,05 Figure 5 St. Jude’s classification of Non-Hodgkin’s lympho- Figure 2 Histopathological classification of Hodgkin’s lym- ma (NHL) according to the clinical stage of disease pro- phoma (HL). gression.

Figure 2 shows number of patients in relation to histopathologi- Figure 5 shows the number of patients classified according to cal type of Hodgkin’s lymphoma. Most patients with HL belonged to the clinical stage of disease progression. Most patients were diag- the histopathological type of nodularsclerosis, 16 (50.0%) patients nosed in stage II, 13 patients (50%) and 8 (30.80%) in stage IV. There and to mixed cellularity, 11 (34.40%) patients. There was statistical- was no statistically significant difference between clinical stages of ly significant difference between the frequency of histopathological NHL (p=0.152, p> 0.05). classifications of patients with HL (p=0.01, p<0.05).

Figure 6 The ten-year survival rate of patients with HL in the period 2004 - 2013.

p=0.239, p > 0,05

Figure 3 Histopathological classification of Non-Hodgkin’s Figure 6 shows the ten year survival rate of patients with HL in lymphoma (NHL). the 2004 - 2013 period, which was 87.50%.

Figure 3 shows the relationship between the two histopatho- logical types of non-Hodgkin’s lymphoma. B-NHL was presentin the majority of patients, 16 patients (61.50%) compared to T-NHL which was present in 10 (38.50%) patients. There was no statistical- ly significant difference between the incidence of histopathological classifications of patients with NHL (p=0.239, p>0.05).

Figure 7 The ten-year survival rate of patients with NHL in

the period 2004 - 2013.

Figure 7 shows the ten year survival rate of patients with NHL in the 2004 - 2013 period, which was 80.77%.

p=0.804, p > 0.05 DISCUSSION Figure 4 Classification of Hodgkin’s lymphoma (HL)- ac In our study, malignant lymphoma was diagnosed in 58 patients, cording to the clinical stage of disease progression (Ann Ar- 37 (63.80%) boys and 21 (36.20%) girls. HL was diagnosed in 32 pa- bor staging classification of Hodgkin’s lymphoma). tients, 17 boys (53.10%) and 15 girls (46.90%), which corresponds Figure 4 shows the number of patients classified according to to the literature stating approximately equal ratio of morbidity in the Ann Arbor staging classification of Hodgkin’s lymphoma. Most boys and girls. NHL was diagnosed in 26 children, 20 boys (76.90%) patients were diagnosed in stage II, 12 patients (37.50%), followed and 6 girls (23.10%). Statistical analysis performed by using Fisher by the 11 patients (34.40%) in stage IV and 9 (28.10%) in stage III. and Chi-square test showed that there was a significant difference There was no statistically significant difference between clinical stag- between the number of boys and girls (p=0.006; Chi-square= es of HL (p=0.804, p> 0.05). 7.538) suffering from NHL. 114 E. Hasanbegović et al.

Pourtsidis A, Pedrosa MF et al. reported 2,5-3 times more af- total of 500 000 children aged 0-15 years in the FB&H and the BD fected boys compared to girls, aged up to 15 years (9, 10). 5.8 suffer from lymphoma, the incidence per 100 000 is 1.38, and The highest number of patients was in the 8 through 15 age 13.80 per million. Of the eleven observed regions, patients from group, 38 children (65.50%). This group included 23 patients seven regions approached the Hematooncology Department of (71.90%) with HL and 15 (57.70%) patients with NHL. In the 2-7 the Pediatric Clinic. There were no cases of malignant lymphoma age group, there were 20 patients, which was 34.50% of all patients. registered in Bosnian Podrinje, Posavina, West Herzegovina Canton Of these, 9 patients were with HL (28.10%), and 11 (42.30%) with and Canton 10. Majority of patients were from Sarajevo Canton, NHL. Statistical analysis showed that there was a significant differ- specifically 16 or 27.60%, 15 or 25.90% of them were from Tuz- ence (p=0.013; Chi-square=6.125) between the age groups of pa- la Canton, 10 or 17.20%, from Zenica-Doboj Canton 7 or 12.10% tients with HL, as well as the difference between the age groups of from Una-Sana Canton, 6 or 10.30% from Central Bosnia Canton, the total number of patients (p=0.018, Chi-square=5.586), which 3 or 5.20% from Herzegovina-Neretva Canton, and 1 or 1.70% of corresponds to the literature. patients were from the Brčko District. The numbers do not indicate Howard SC, Metzger ML et al. stated that the greatest incidence a special concentration of patients in certain cantons except for Sa- of HL and NHL was in the age group of 2-10 years, rarely occured rajevo Canton, where 16 patients were registered (10 patients with before the age of two, and more often after the age of ten (11). NHL and 6 with HL). These results are largely attributed to demo- There was no statistically significant difference between the age graphic factors. groups of patients with NHL (p=0.43, Chi-square=0.615) in our The main clinical symptom dominant in HL and NHL was pain- study. less enlargement of the lymph nodes (lymphadenopathy). In chil- Total of 401 patient was treated of malignancies. Majority of dren with HL lymphadenopathy it was present in 26 cases, and in them were treated of leukemia, 157 patients (39.20%), followed by children with NHL in 19 cases. After lymphadenopathy, the most lymphoma, 58 (14.50%), brain tumors 41 (10.20%), neuroblastoma common associated symptoms were subfebrile temperature: HL 9, 38 (9.50%), other tumors 30 (7.50%), sarcoma 29 (7.20%), nephro- NHL 10; hepatosplenomegaly: HL 7, NHL6; and weight loss: HL 7, blastoma 26 (6.50%) and 22 (5.50%) patients were treated of bone NHL 5 (all these symptoms occured equally). The difference be- tumors. tween HL and NHL was noted in the occurrence of symptoms such Konja J et al. reported that in the world, the highest number of as loss of appetite, paleness, weakness, cough and pain in the bones. children were suffering from leukemia, followed by brain tumors in Thus, for example, in HL: 7 patients suffered from loss of appetite the second place and malignant lymphomas in the third place (12). and 11 from paleness, compared to NHL where 3 patients suffered Our results do not correspond to the results of the cited literature. from loss of appetite and 5 from paleness. The symptoms in NHL The main reason for discrepancies lies in the fact that this research occurred more symptomatologically such as weakness in 8 patients, covered a small area, in this case, the Federation of Bosnia and Her- cough in 6, pain in the bones in 5 patients, compared to HL where zegovina and the Brčko District. Therefore, to cover a larger area, cases of weakness were registered in 4 patients, coughin 3 and pain e.g. Southeastern Europe, it is assumed that the results would be in the bones 1 patient. The difference was evident, but not so rele- consistent with the pre-mentioned literature, i.e. lymphomas would vant for statistically significant difference. be in the third place. Schwartz CL, Büyükpakmukcu M, et al. reported that the most Most new cases of malignant lymphoma were diagnosed in common symptoms of lymphoma were lymphadenopathy, fever, 2013, 10 (17.20%), in 2005, 9 patients (15.50%), 8 (13.80%) in 2004, loss of appetite, weight loss, weakness with night sweating and itch- 2006, 2007, and, 6 (10.30%) patientsin 2011. In other years, the iness of the skin (1, 14). number of new cases did not exceed 5 per year, even in 2008 there The following non-specific laboratory parameters of lymphoma were nonew cases of HL, and only 1 case of NHL was registered. were monitored: lactate dehydrogenase (LDH), ferritin, β2-globulin Majority of new cases of HL, 7 patients (21.90%), were registered and cuprum (Cu) in serum (2). The increase in their values indicated in 2005, and of NHL in 2013, 6 (23.10%) patients. The total num- to the worsening of the disease and its activity. LDH was elevated ber of patients with lymphoma in the Federation of B&H and the in 16 cases of HL and in 14 cases of NHL. Ferritin was elevated in 4 Brčko District for the period of 10 years amounted to 58 patients, patients with HL and in 1 patient with NHL. β2-globulin was elevat- anaverage of 5.8 patients per new case. Incidence for the same area ed in five patients with HL and in 4 with NHL, and Cu serum levels amounted to 2.32 per million out of the total number of population in 15 patients with HL and 10 patients with NHL. There was no sta- (according to the assessment FB&H and the Brčko District have 2.5 tistically significant difference between the two groups of patients. million people), or 0.232 per 100 000 population. Children’s Cancer The study conducted by Sanjay Vinjamaram MD et al. found that Institute Australia, headed by Baade PD stated that in Australia for laboratory parameters in NHL such as LDH, β2-globulin, serum Cu the period of 1997-2006, the number of new registered cases was were significant during the screening test, in monitoring the effects an average of 62 per year, and the total number of patients for a of therapy to the final cure. Ye QD, Pan C, et al. confirmed that period of 10 years amounted to 620. The incidence of childhood laboratory parameters in HL, LDH, serum Cu, ferritin, β2-globulin lymphoma for the same period of 10 years in Australia was 2.70% were very important for prognosis, course and outcome of disease. per 1 million population, or 0.270 per 100 000 population (if we These two studies showed that these laboratory parameters for take that Australia has about 23 million population). Thus, it can be both, HL and NHL, played a very important role in monitoring the concluded that the incidence of childhood lymphoma in the FB&H disease and that there was no statistically significant difference be- and the BD is less than in Australia for 0.38% per million population, tween subtypes of lymphoma, which is consistent with our research or 0.038 per 100 000 population (13). According to our data, out of (15, 16). Epidemiological and clinical characteristics of childhood lymphoma 115

From the point of pathohistology REAL (Revised Europe- REFERENCES an-American Lymphoma) classification is currently in use, modified and accepted by the World Health Organization (WHO), which dif- 1. Büyükpakmukcu M. Non-Hodgkin’s lymphomas. In: Cancer in Children: Clinical fers nodular form of lymphocyte predomination and classical Hod- manegment. Fourth Edition, Voute P.A., Kalifa C, Barrett A. Eds. Oxford, Oxford gkin’s lymphoma. University Press 1999: 119-136. 2. Pizzo A, Poplack GD. Principles of Pediatric Oncology. 5rd ed. Philadelphia: Lippin- Classical HL is divided into nodular sclerosis, lymphocyte pre- cott Williams - Wilkins; 2005. domination, mixed cellularity and lymphocyte depletion. It was 3. Saunders C. Hsu, Monika L. Metzger, Melissa M. Hudson et al. Comparison of noticed that most cases had nodular sclerosis, 16 cases (50.0%), Treatment Outcomes of Childhood Hodgkin Lymphoma in Two US Centers and a followed by mixed cellularity in 11 patients (34.4%), while the lym- Center in Recife, Brazil. Pediatric Blood Cancer 2007;49:139-144. phocyte predomination and depletion were represented in a small- 4. DeVita VT. A selective history of the therapy of Hodgkin’s disease. Br J Hematol er number. There was statistically significant difference between 2002; 122: 718-727. the incidence of histopathologic classifications of patients with HL 5. Thomson AB, Wallace WHB. Treatment of paediatric Hodgkin’s disease: a balance of risks. Eu J Cancer 2002 Mar; 38(4): 468-77. (p=0.01, p<0.05). Obralić et al. reported that the most common 6. Vats TS. Pediatric Non-Hodgkin’s lymphomas in children: Diagnosis and current was nodular type, with the representation of 40-70%, followed by management. Indian Pediatrics 2001 Jun; 38(6): 583-8. mixed cellularity (30-50%), lymphocyte predomination (5-10%) and 7. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine lymphocyte depletion with 1-5% (17). Our results correlate with the E. 6. London: BC Decker Inc, 2003; 374-87. results in the international literature. 8. Hasanbegović E, Šabanović S. The results of Hodgkin lymphoma treatment in chil- Out of 26 patients with NHL, 16 (61.50%) had B-NHL, and dren in the period 1997.-2006. Bosn J Basic Med. 2008 Feb;8(1): 72-5. 10 patients (38.50%) T-NHL. Murphy SB, et al reported the inci- 9. Pourtsidis A, Doganis D, Baka M, Bouhoutsou D, Varvoutsi M, Synodinou M, et al Differences between younger and older patients with childhood Hodgkin lympho- dence of B-NHL > 60%, or more precisely (65-70%), and of T-NHL ma. Pediatr Hematol Oncol. 2013 Sep; 30(6): 532-6 <40%, or more precisely (30-35%) (18). The results of our study 10. Pedrosa MF, Pedrosa F, Lins MM, Pontes Neto NT, Falbo GH. Non-Hodgkin’s lym- are approximate to the relevant literature. According to the clinical phoma in childhood: clinical and epidemiological characteristics and survival analysis stage of disease progression, Hodgkin’s lymphoma was classified by at a single center in Northeast Brazil. J Pediatr (Rio J). 2007 Nov-Dec; 83(6): 547-54. the Ann Arbor classification system. Majority of new cases were 11. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine diagnosed in stage II of disease, 12 (37.50%), then in stage IV, 11 E. 6. London: BC Decker Inc, 2003; 374-87. (34.40%), and in stage III 9 patients (28.10%). There was not diag- 12. J. Konja i sur. Maligni limfomi. Paediatr Croat 2006; 50 (Supl 1): 198-202. 13. BaadePD, Youlden DR, Valery PC, Hassall T, Ward L, Green AC et al, Trends nosed cases of HL in the first stage. in incidence of childhood cancer in Australia, 1983–2006.Br J Cancer. 2010 Feb Xing PY et al. noted that patients diagnosed with HL were 2;102(3):620-6; Average annual incidence for lymphoma, 1997-2006; British Journal 28.40% in stage I, 34.80% in stage II, 19.70% and 17.10% in stage III of Cancer (2010) 102, 620–626. and IV (19). According to our research, most of Hodgkin’s lympho- 14. Schwartz CL. The management of Hodgkin disease in the young child. Curr Opin ma (HL) was diagnosed in stage II and IV, while based on interna- Pediatr. 2003 Feb; 15(1): 10-6. tional literature, HL in children was most represented in the first and 15. Sanjay Vinjamaram, MD, MPH. Diagnosis signs and symptoms, laboratory studies in second stage. According to the clinical stage of disease progression, a patient with suspected NHL. Sep 20 2006;24(27):4418-25. 16. Ye QD, Pan C, Xue HL, Chen J, Zhou M, Jiang H, Shen SH, Tang YJ, Wang JM. De- non-Hodgkin’s lymphoma was classified by St. Jude’s classification partment of Hematology/Oncology, Shanghai Children’s Medical Center, Shanghai system. The highest number of new cases were diagnosed at the Jiaotong University School of Medicine, Shanghai 200127, China. time when they were already in stage II of disease, 13 (50%). There 17. Obralić N. Limfomi: Morbus Hodgkin, non-Hodgkin limfomi. U Mušanović M, Obralić were 8 (30.80%) patients in stage IV and 5 (19.20%) in stage III. N: Onkologija. Bošnjački institut, Sarajevo, Bosna i Herzegovina, 2002; 373-396. Adamson P, Murphy et al. reported the results according to 18. Murphy SB. Classification, staging and results of treatment of childhood non-Hod- stages: I (18%), II (21%), III (43%) and IV (18%) (20). gkin’s lymphomas in adults. Semi Oncol 1980 Sept; 7(3):332-9. Non-Hodgkin’s lymphoma (NHL) according to our results was 19. Xing PY, Shi YK, He XH, Zhou LQ, Dong M, Yang JL, Liu P. Clinical analysis of child- hood and adolescent Hodgkin’s lymphoma: a report of 88 cases. Zhonghua Zhong the most represented in the second stage, while according to rele- Liu Za Zhi. 2012 Sep; 34(9): 692-7. doi: 10.3760/cma.j.issn.0253-3766.2012.09.011. vant international literature, NHL was the most common in stage III. 20. Adamson P, Bray F, Costantini AS, Tao MH, Weiderpass E, Roman E. Time trends in In our study, ten-year survival of patients with HL was 87.50% and the registration of Hodgkin and non-Hodgkin lymphomas in Europe. Eur J Cancer 80.77% with NHL. These results were approximate to the data that 2007 Jan;43(2):391-401. Lee SH, Xing PY, et al. noted (21, 19). 21. Lee SH, Yoo KH, Sung KW, Ko YH, Lee JW, Koo HH. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Re- public of Korea. Pediatr Blood Cancer. 2013 Nov;60(11):1842-7. doi: 10.1002/ CONCLUSION pbc.24695. Epub 2013 Jul 16.

Lymphomas are the second malignancies in children at the Pe- diatric Clinic of CCUS. Most patients are in the age group of 8-15 years, with higher percentage prevalence of boys compared to girls. Reprint requests and correspondence: Edo Hasanbegović, MD, PhD Clinical diagnostic methods and modern therapy at the Pediatric Pediatric Clinic Clinic contribute to the good prognosis for patients suffering from Clinical Center University of Sarajevo lymphoma in childhood. The survival rates of patients are similar to Patriotske lige 81, 71000 Sarajevo those in international centres. Bosnia and Herzegovina Phone: +387 33 566 448 Conflict of interest: none declared. Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 116 - 119 Original article Secondary osteoporosis in hospital sample Sekundarna osteoporoza u bolničkom uzorku

Ksenija Miladinović1*, Narcisa Vavra-Hadžiahmetović1, Slavica Šakota1, Damir Čelik1, Haris Tanović2

1Clinic of Physical and Rehabilitation Medicine, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of General and Abdominal Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: secondary osteoporosis still remains subdiag- Uvod: sekundarna osteoporoza je još uvijek subdijagnosticiran nosed entity. According to previous studies in certain diseases such entitet. Dosadašnje studije pokazuju da je dijagnoza i liječenje as multiple sclerosis, spinal cord lesion, diabetes mellitus, rheuma- sekundarne osteoporoze veoma važno kod odredjenih bolesti toid arthritis, malignomas, chronic kidney disease, as well as in con- kao što su: multipla skleroza, spinalna lezija, diabetes melitus, dition after hysterectomy, diagnosis and treatment of secondary reumatoidni artritis, malignomi, hronične bolesti bubrega, kao osteoporosis is very important. Objective: the aim of this study was i stanje nakon histerektomije. Cilj: ova studija je imala za cilj da to analyze the pattern of hospital patients who had the diseases analizira uzorak bolničkih pacijenata koji su imali bolesti gdje se where development of secondary osteoporosis was expected. Ma- očekuje razvoj sekundarne osteoporoze. Materijal i metode: iz therial and Methods: out of all medical records of the patients who medicinske dokumentacije svih pacijenata koji se hospitalizirani na were treated at the inpatient Clinic of Physical and Rehabilitation Klinici za fizijatriju i rehabilitaciju Univerzitetskog Kliničkog Centra u Medicine (n=531) from November 2012 to November 2013, the Sarajevu (n=531) od novembra 2012. do novembra 2013. godine, patients who had the diseases, where development of secondary izdvojeni su pacijenti koji su imali bolesti kod kojih se očekivao razvoj osteoporosis was expected, were selected, and these were: mul- sekundarne osteoporoze, a to su bile: multipla skleroza, spinalna tiple sclerosis, spinal lesion, diabetes mellitus, rheumatoid arthritis, lezija, diabetes melitus, reumatoidni artritis, malignomi, hronične malignant disease, chronic kidney disease, as well as condition after bolesti bubrega, kao i stanje nakon histerektomije. Pacijenti su zatim hysterectomy. Patients were divided in two groups. The first group podijeljeni u dvije grupe. Prvu grupu (I) su sačinjavali oni pacijenti (I) consisted of patients to whom secondary osteoporosis was diag- kod kojih je dijagnosticirana i tretirana sekundarna osteoporoza, a nosed and treated, and the second group (II) consisted of patients drugu grupu (II) pacijenti kod kojih nisu provedene dijagnostičke to whom diagnostic procedures for secondary osteoporosis were procedure za sekundarnu osteoporozu, iako su po kliničkoj slici i not performed, although according to clinical picture and to primary primarnoj bolesti bili potencijalni kandidati da je imaju. Rezultati: od disease they were potential candidates. Results: out of total num- ukupnog broja hospitaliziranih pacijenata (n=531), 13.2% (n=70) ber of hospitalized patients (n=531), 13.2% (n=70) had the diseases je imalo primarnu bolest kod koje se očekuje razvoj sekundarne where development of secondary osteoporosis was expected. In osteoporoze. Kod 20% od ovih pacijenata sekundarna osteoporoza 20% of these patients secondary osteoporosis was diagnosed and je bila dijagnosticirana i tretirana, (grupa I). U ovoj grupi najčešća treated, and they presented the first group (I). In this group the primarna bolest je bila spinalna lezija, 57.1% (n=8), praćena sa most frequent disease was spinal lesion, presented by 57.1% (n=8), multiplom sklerozom i reumatoidnim artritisom, 14.3% (n=2) svaka, followed by multiple sclerosis and rheumatoid arthritis with 14.3% zatim sa hroničnom bubrežnom bolešću i malignitetima, 7.1% (n=1) (n=2) each, then chronic kidney disease and malignant disease with svaka. Muškarci su sačinjavali 42.8% (n=6) ove grupe. Grupa II je 7.1% (n=1) each. Male patients formed 42.8% (n=6) of this group. bila predstavljena sa 80% selektiranih pacijenata (n=56) koji su The second group (II) was presented by 80% of selected patients imali primarne bolesti kod kojih se očekivao razvoj sekundarne (n=56) with primary disease where development of secondary osteoporoze, ali im nije uradjena dijagnostika za postojanje iste. U osteoporosis was expected, but they were not diagnosticaly pro- ovoj grupi najčešća primarna bolest je bila multipla skleroza, 39.3% cessed. In this group the most frequent disease was multiple sclero- (n=22), praćena sa malignomima, 26.76% (n=15), zatim sa spinalnom sis, presented by 39.3% (n=22), followed by malignoma with 26.76% lezijom i diabetes melitusom sa 10.7% (n=6) svaka, stanjem nakon (n=15), then spinal lesion and diabetes mellitus with 10.7% (n=6) histerektomije sa 8.8% (n=5) i reumatoidnim artritisom sa 3.6% each, condition after hysterectomy with 8.8% (n=5) and rheumatoid (n=2). Odnos žena i muškaraca je bio 1:1. Zaključak: pacijenti sa arthritis with 3.6% (n=2). Ratio between males and females was 1:1. odredjenim oboljenjima kao što su multipla skleroza, spinalna lezija, Conclusion: patients with certain diseases, like multiple sclerosis, diabetes melitus, reumatoidni artritis, malignomi, hronične bolesti spinal cord lesion, diabetes mellitus, rheumatoid arthritis, malignant bubrega, kao i stanje nakon histerektomije, bez obzira na stadij disease, chronic kidney disease, as well as condition after hysterec- bolesti, zahtijevaju više inicijative za dijagnosticiranje sekundarne tomy, regardless of stage and time of disease occurance, demand osteoporoze. higher attention for secondary osteoporosis diagnostic processing.

Key words: secondary osteoporosis, diagnostic processing Ključna riječ: sekundarna osteoporoza, dijagnostičke procedure Secondary osteoporosis in hospital sample 117

INTRODUCTION both sexes. (3) The physical as well as pharmacological interventions which can Osteoporosis that results from having another disease or condi- counteract the bone remodeling imbalance, particularly osteocyte tion or from the treatment of another condition is called second- apoptosis, are promising for prevention and treatment of osteopo- ary osteoporosis. Secondary osteoporosis remains a diagnostic and rosis in patients with MS. therapeutic challenge as it frequently affects patient populations, e.g. Osteoporosis related to spinal lesion; osteoporosis induced premenopausal women or younger men who are usually not target by spinal lesion (SL) is, actually, inevitable complication, which begins populations for routine screening for osteoporosis. to develop already tenth day after occurrence of spinal lesion, reach- A variety of diseases or conditions can increase bone loss and/ es its maximum after 4-6 months, then stabilizes after 12-16 months. or fall risk, such as: rheumatoid arthritis and other rheumatological It occurs predominantly in the pelvis and the lower extremities, and conditions, neurological disorders (stroke, multiple sclerosis, spinal is found in 60-90% of patients with SL. (4) Mechanism of spinal lesion lesion, Parkinson’s disease, cerebral palsy, neuropathy), malabsorp- induced osteoporosis development is complex. Initially it has been tion syndromes, sex hormone deficiency, primary hyperparathyroid- studied in the light of altered metabolism of calcium and hypercal- ism, chronic kidney disease, chronic liver disease, diabetes, chronic cemia, associated hypercalcuria and the loss of load. Multifactorial obstructive pulmonary disease or hyperthyroidism. Medications that mechanism of its formation, both in acute and in chronic phase of can cause bone loss, falls and/or fractures are: synthetic glucocorti- SL, is examined in detail only in the last ten years. In addition to neu- coids (e.g. prednisone), breast cancer drugs, prostate cancer drugs, rological changes caused by spinal cord lesion, especially interruption “heartburn” drugs, excessive thyroid hormone replacement, anti-sei- of pathways which are involved in bone innervation, affection factors zure and mood-altering drugs, blood pressure medication, diuretics, may include abnormalities of blood flow in infralesion levels that in- prostate drugs, and others drugs. Management of secondary osteo- fluence bone cell differentiation, and hormonal changes that generate porosis includes treatment of the underlying disease, modification of metabolic bone disorder. In the chronic phase of SL osteoporosis is medications known to affect the skeleton, and specific anti-osteopo- balanced by increasing bone mineral density in regions of the body rotic therapy. that are burdened by their own weight, like upper extremities and It is very important to diagnose and treat secondary osteoporosis, the spine, and even by greater demineralization of regions that are otherwise falls and fractures, as well as visceral and heterotopic calcu- chronically without a load, such as pelvis and lower extremities. Oste- losis, reduce already compromised quality of life of these patients. oporosis induced by SL has been successfully treated with physical as Osteoporosis related to rheumatoid arthritis and oth- well as pharmacological interventions which can counteract the bone er rheumatological conditions; an inflammatory disease of the remodeling imbalance, such as bisphosphonates or denosumab. joints, rheumatoid arthritis (RA) is often treated with glucocorticoids, Osteoporosis related to malignant disease; patients with usually prednisone. Pain and loss of joint function can lead to inactiv- cancer may be at risk for secondary osteoporosis related to cancer ity, which can further contribute to bone loss. Research suggests that therapies, particularly therapies that impair gonadal function. Patients osteoclast activity and bone resorption is increased at the affected with cancers such as breast or prostate cancer who have been treated sites. During the pathological processes, inflammatory cytokines such with hormone deprivation therapies or anti-cancer agents for certain as TNF (tumor necrosis factor) are largely produced from inflamed periods of time frequently manifest reduced bone mass or pathologi- synovium and cause activation of osteoclasts deviated from bone re- cal fractures during their clinical course. These are likely due to an im- modeling cycle. (1) Osteoporosis in RA is characterized by bone loss balance between osteoblastic bone formation and osteoclastic bone in the hip and the radius, while the axial bone is relatively preserved. resorption. (5) Bone should be carefully monitored in these patients. Bisphosphonates are well known to be effective for not only treat- Identifying which patients with cancer are at risk for bone mineral ment but also prevention of glucocorticoid-induced osteoporosis. In density loss is important, and beside patients with breast or prostate addition to rheumatoid arthritis, ankylosing spondylitis has been associ- cancer, may include adults with other tumors and some survivors of ated with bone loss. Several other rheumatologic conditions may affect pediatric malignancies. (6) Osteoporosis among cancer survivors is the joints, resulting in poor balance and increased risk of falls, including higher in elderly subjects and in female cancer survivors (95%). In lupus, psoriatic arthritis and severe osteoarthritis of the hip or knee. male cancer survivors, underweight and lower calcium intake are risk Osteoporosis related to multiple sclerosis; multiple scle- factors. (7) Administration of some agents, such as bisphosphonates rosis (MS) is disorder characterized by acute episodes of neurolog- or denosumab, may be necessary to maintain bone mineral density ical defects leading to progressive disability. Patients with MS have and protect pathological fractures in these cancer patients. multiple risk factors for osteoporotic fractures, such as progressive Osteoporosis related to diabetes mellitus; diabetes mel- immobilization, long-term glucocorticoids treatment or vitamin D litus is a risk factor for osteoporotic fractures. Patients with recent deficiency. The duration of motor disability appears to be a major onset of type 1 diabetes mellitus may have impaired bone formation contributor to the reduction of bone strength. The long term immo- because of the absence of the anabolic effects of insulin and amylin, bilization causes a marked imbalance between bone formation and whereas in long-standing type 1 diabetes mellitus, vascular compli- resorption with depressed bone formation and a marked disruption cations may account for low bone mass and increased fracture risk. of mechanosensory network of tightly connected osteocytes due to Patients with type 2 diabetes mellitus display an increased fracture risk increase of osteocyte apoptosis. Vertebral BMD is affected to a lesser despite a higher BMD, which is mainly attributable to the increased degree than femoral BMD. Patients with higher level of disability have risk of falling. (8) Strategies to improve BMD and to prevent osteo- also higher risk of falls that combined with a bone loss increases the porotic fractures in patients with type 1 diabetes mellitus may include frequency of bone fractures. The low BMD in MS patients involve optimal glycemic control and aggressive prevention and treatment of 118 K. Miladinović et al. vascular complications. Patients with type 2 diabetes mellitus (T2DM) may additionally benefit from early visual assessment, regular exercise to improve muscle strength and balance, and specific measures for preventing falls, as well as from calcium and vitamin D rich diet. The prevalence of low BMD in males with T2DM is 59.1% according to recent study (9). Osteoporosis related to chronic kidney disease; changes in mineral metabolism and bone structure develop early in the course of chronic kidney disease and worsen with progressive loss of kid- ney function. Chronic kidney disease (CKD) includes abnormalities of calcium, phosphorus, parathyroid hormone, or vitamin D, abnor- malities in bone turnover, mineralization, volume, linear growth, or Figure 1 Percantage of patients with diseases in wich devel- strength, and vascular or other soft tissue calcification (10). Patients opment of secondary osteoporosis is expected. with chronic kidney disease may have other bone diseases (osteopo- rosis, vitamin D deficiency) either before or after developing kidney Male patients formed 42.8% (n=6) of this group. disease. It is difficult to diagnose osteoporosis in the setting of CKD. This is particularly relevant for the aging population, where fragility The second group (II) was presented by 80% of selected patients fractures, reduced glomerular filtration rate (GFR), and low bone (n=56) with primary disease where development of secondary os- mineral density are more prevalent. There are multiple reasons why teoporosis is expected, but they were not diagnosticaly processed this differentiation is important, not the least of which is that man- (Figure 2). agement of osteoporosis versus the spectrum of bone diseases in patients with CKD differ vastly. Osteoporosis related to hysterectomy; it is very well known that osteoporosis and increased risk of bone fractures are associat- ed with hysterectomies. This has been attributed to the modulatory effect of estrogen on calcium metabolism, and the drop in serum es- trogen levels after menopause can cause excessive loss of calcium leading to bone wasting. Strategies to improve BMD and to prevent fracture are based on hormone replacement therapy (HRT), calcium and vitamin D, or other type of drugs for osteoporosis.

MATERIALS AND METHODS Figure 2 Percantage of patients with diagnosed ant treated secondary osteoporosis and of patients who were not diag- Out of all medical records of the patients who were treated at nosticaly processed. the Clinic of Physical and Rehabilitation Medicine (n=531) from No- vember 2012 to November 2013, the patients who had the diseases where development of secondary osteoporosis was expected were In this group the most frequent disease was multiple sclerosis, pre- selected, and these were: multiple sclerosis, spinal lesion, diabetes sented by 39.3% (n=22), followed by malignoma with 26.8% (n=15), mellitus, rheumatoid arthritis, malignant disease, chronic kidney dis- ease, as well as condition after hysterectomy. Patients were divided in two groups. The first group consisted of patients whom second- ary osteoporosis was diagnosed and treated (I). The second group (II) consisted of patients whom diagnostic procedures for secondary osteoporosis presence were not performed, although according to clinical picture and to primary disease they were potential candidates.

RESULTS

Out of total number of hospitalized patients (n=531), 13.2% (n=70) had the diseases where development of secondary osteopo- rosis was expected (Figure 1). Figure 3 Diseases related to diagnosed and treated second- In 20% of these patients secondary osteoporosis was diagnosed ary osteoporosis. and treated, and they presented the first group (I) (Figure 2). In this group the most frequent disease was spinal lesion, present- then spinal lesion and diabetes mellitus with 10.7% (n=6) each, con- ed by 57.1% (n=8), followed by multiple sclerosis and rheumatoid dition after hysterectomy with 8.8% (n=5) and rheumatoid arthritis arthritis with 14.3% (n=2) each, then chronic kidney disease and ma- with 3.6% (n=2) (Figure 4). lignoma with 7.1% (n=1) each (Figure 3). Ratio between males and females was 1:1. Secondary osteoporosis in hospital sample 119

12-fold higher risk of sustaining osteoporotic fractures, compared with non-diabetic controls. (12) In our sample diabetes mellitus was not presented in the first group (I) at all, and in the second group it was presented by 10.7% (n=6). Several cross-sectional studies doc- umented a lower mineral bone density in patients with RA, with a two-fold increase in osteoporosis compared to age and sex matched controls. (2) In the first group (I) of selected patients in our analy- sis rheumatoid arthritis was presented with 14.3% (n=2), and in the second group (II) with 3.6% (n=2). It is very important to prevent and treat bone loss after hysterectomy because of high risk for os- teoporotic fractures. Our hospital sample showed that there were 8.8% (n=5) of women with hysterectomy in the second (II) group of Figure 4 Diseases related to diagnosticaly not processed secondary osteoporosis. patients, and that condition was not present in the first group (I).

DISCUSSION CONCLUSION

Secondary osteoporosis is characterized by low bone mass with Patients with certain diseases, like multiple sclerosis, spinal cord le- microarchitectural alterations in bone leading to fragility fractures in sion, diabetes mellitus, rheumatoid arthritis, malignant disease, chron- the presence of an underlying disease or medication. ic kidney disease, as well as condition after hysterectomy, regardless An open-minded approach with a detailed history and physical of stage and time of disease occurance, demand higher attention for examination combined with first-line laboratory tests are aimed at secondary osteoporosis diagnostic processing. identifying clinical risk factors for fractures, osteoporosis-inducing drugs, and underlying endocrine, gastrointestinal, hematologic, or Conflict of interest: none declared. rheumatic diseases, which then need to be confirmed by specific and/or more invasive tests. Bone mineral density should be assessed REFERENCES with bone densitometry at the hip and spine. Lateral X-rays of the 1. Tanaka Y. Rheumatoid arthritis and bone damage: trends in treatment. Clin Calci- thoracic and lumbar spine should be performed to identify or ex- um.2010 May; 20(5):735-42. clude prevalent vertebral fractures which may be clinically silent. (11) 2. Vosse D, de Vlam K. Osteoporosis in rheumatoid arthritis and ankylosing spondylitis. In our hospital sample 20% of patients (I group) were diagnosed and Clin Exp Rheumatol 2009 Jul-Aug; 27(4 Suppl 55):S62-7. treated for secondary osteoporosis, and 80% of patients (II group) 3. Marrie RA, Cutter G, Tyry T, Vollmer T. A cross-sectional study of bone health in (n=56), with primary disease where development of secondary os- multiple sclerosis. Neurology 2009 Oct 27;73(17):1394–8. teoporosis was expected, were not diagnosticaly processed. The 4. Lin VWH, Cardenas DD, Cutter NC, Frost FS, Hammond MC (2002). Spinal Cord Medicine: Principles and Practice. Demos Medical Publishing most frequent primary disease in group I was spinal lesion, present- 5. Yoneda T. Pathophysiology and management of cancer treatment-induced bone ed by 57.1% (n=8), followed by multiple sclerosis and rheumatoid loss/fractures. Clin Calcium. 2010 May;20(5):690-9 arthritis with 14.3% (n=2) each, then chronic kidney disease and 6. Wickham R. Osteoporosis Related to Disease or Therapy in Patients With Cancer. malignoma with 7.1% (n=1) each. Rather high percentage (80%) of Clin J Oncol Nurs. 2011 Dec;15(6). patients were not diagnosticaly processed for secondary osteopo- 7. Choi KH, Park SM, Park JS, Park JH, Kim KH, Kim MJ. Prevalence of and factors as- rosis, even though they had primary disease where development of sociated with osteoporosis among Korean cancer survivors: a cross-sectional analysis secondary osteoporosis was expected. The most frequent disease of the Fourth and Fifth Korea National Health and Nutrition Examination Surveys. Asian Pac J Cancer Prev. 2013;14(8):4743-50. in this group (II) was multiple sclerosis, presented by 39.3% (n=22), 8. Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabe- followed by malignoma with 26.76% (n=15), then spinal lesion and tes mellitus. J Bone Miner Res.2007 Sep;22(9):1317-28. diabetes mellitus with 10.7% (n=6) each, hysterectomy with 8.8% 9. Chen HL, Deng LL, Li JF. Prevalence of Osteoporosis and Its Associated Factors (n=5) and rheumatoid arthritis with 3.6% (n=2). among Older Men with Type 2 Diabetes. Int J Endocrinol. 2013(2013):285729. Patients with MS have multiple risk factors for osteoporotic frac- 10. Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K,et all. Definition, tures, such as progressive immobilization, long-term glucocorticoids evaluation, and classification of renal osteodystrophy: a position statement from Kidney treatment or vitamin D deficiency. The analysis of a registry of 9029 Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006 Jun;69(11):1945-53. 11. Hofbauer LC, Hamann C, Ebeling PR. Approach to the patient with secondary oste- patients with MS in the USA found that 27.2% responders reported oporosis. Eur J Endocrinol. 2010 Jun;162(6):1009-20. low bone mass, and more than 15% of responders reported a history 12. Nicodemus KK, Folsom AR; Iowa Women’s Health Study. Type 1 and type diabetes and of fracture. (3) In our sample multiple sclerosis was presented with incident hip fractures in postmenopausal women. Diabetes Care 2001;24(7):1192–7. 14.3% in the first (I) group of patients and with 39.3% in the second group (II). Osteoporosis induced by spinal lesion (SL) is found in 60- 90% of patients with. (4) In our analysis the most frequent primary Reprint requests and correspondence: disease was spinal lesion in group I, presented by 57.1% (n=8). In the Ksenija Miladinović, MD Clinic of Physical and Rehabilitation Medicine second group osteoporosis induced by SL was presented by 10.7% Clinical Centre University of Sarajevo (n=6). Bolnička 25, 71000 Sarajevo The adverse effects of diabetes mellitus have just recently been Bosnia and Herzegovina acknowledged. In fact, patients with type 1 diabetes mellitus have a Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 120 - 123 Professional article Most common etiologies of neurogenic laryngeal paralysis in middle-aged patients Najčešći uzroci neurogenih paraliza larinksa kod pacijenata srednje životne dobi

Mirjana Gnjatić1*, Daniela Kesić Mijić2, Tatjana Barać3, Svjetlana Trifunović2

1Ear, Nose and Throat Clinic, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina; 2Outpatient Department Banja Luka, Sime Matavulja bb, 78000 Banja Luka, Bosnia and Herzegovina; 3Department of Gastroenterology, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: a large number of causes lead to neurogenic laryn- Uvod: veliki je broj uzročnika neurogenih paraliza larinksa, koje geal paralysis, which is expressed as impairment of certain laryngeal se očituju kao smanjenom funkcijom određenih laringealnih mišića, muscles function and manifested as hoarseness and dysphonia. Neu- a koja se manifestuje kao promuklost i disfonija. Neurogene paralize rogenic laryngeal paralyses are the matter of interest and research for larinksa su predmet interesovanja i istraživanja otorinolaringologa otolaryngologists, because of complex etiology, precise evaluation, as zbog svoje kompleksne etiologije, potrebne precizne evaluacije, di- well as diagnostics, and especially because of the long and complicated jagnostičke obrade, a posebno zbog duge i komplikovane terapije. treatment. Aim: determine the prevalence of etiological factors and Cilj rada: odrediti prevalence etioloških faktora i simptoma jednos- symptoms of unilateral and bilateral neurogenic paralysis of the larynx trane i obostrane neurogene paralize glasnica u larinksu (pol, dob) i (gender, age) and their differences. Materials and methods: we have njihove razlike. Materijal i metode: trogodišnja prospektivna studija performed a three-year prospective study in the Clinical Center Banja je sprovedena u Kliničkom Centru u Banjaluci koja je uključivala 110 Luka which included 110 patients in Ear, Nose and Throat Clinic, Clin- pacijenata Otorinolaringološke klinike, Kliničkog Centra Banjaluka. ical Center Banja Luka. The patients were monitored in the phoniatric Pacijenti su praćeni u fonijatrijskom kabinetu, gdje su, endovideos- cabinet where, the types of paralysis were determined by means of troboskopskom metodom, određivani tipovi paraliza i, kroz upit- the endo-videostrobescope, and etiological causes by means of the nike, utvrđeni etiološki uzroci. Dobijeni rezultati su obrađeni stan- questionnaires. The obtained results were analyzed by using standard dardnim statističkim metodama – X2 test, Studentov test. Rezultati: statistical methods - X² test, Student test. Results: the study included a Ukupan broj pacijenta u ovoj studiji iznosio je 110, od čega je 70.9% total of 110 patients, of which 70.9% were females and 29.9% males. bilo ženskog, a 29.9% muškog pola. Pokazalo se da su 92 pacijen- It appeared that 92 patients had unilateral vocal cord paralysis while ta imali jednostranu, a 18 obostranu paralizu glasnica – pretežno 18 had bilateral, mainly in the female population. Complications after u ženskoj populaciji. Komplikacije nakon operacije štitne žlijezde su the thyroid gland surgery were the leading etiologic factor in the de- bile vodeći faktor u razvoju obostranih neurogenih paraliza glasni- velopment of bilateral neurogenic paralysis of the larynx. Conclusion: ca larinksa. Zaključak: naše istraživanje nas je dovelo do zaključka our research resulted in a conclusion that the leading factor in the life da vodeći faktor u razvoju obostrane paralize glasnica, a koji može threatening bilateral paralysis development is a thyroid gland surgery i ugroziti život pacijenta, jeste operacija štitne žlijezde (zbog pov- (due to the increase in malignant disease of the thyroid gland, which is ećanog maligniteta štitnjače što predstavlja dodatan rizik pred hiruški an additional risk for surgical treatment), as well as the operation risks. zahvat), kao i operativni rizici.

Keywords: neurogenic laryngeal paralysis, unilateral paralysis, bilater- Ključne riječi: neurogena laringealna paraliza, jednostrana parali- al paralysis, etiology za, obostrana paraliza, etiologija

INTRODUCTION es 5) prolonged intubation 6) lung cancer 7) esophageal cancer 8) idiopathic paralysis. Neurogenic laryngeal paralyses are the matter Larynx, as one of the functionally most perfect human organs, of interest and research for otolaryngologists, because of complex with its highly specialized features sounds as an intellectually con- etiology, precise evaluation, as well as diagnostics, and especially be- scious being. From the time of Hippocrates (460-370 BC) it was cause of the long and complicated treatment (5,6). observed that denervation of the larynx had life-threatening con- Neurogenic laryngeal paralysis (unilateral and bilateral vocal cord sequences (1,2,3,4). A large number of causes lead to neurogenic paralysis), along with numerous other disorders, is one of the most laryngeal paralysis, which can be seen as a failure of certain functions common reasons for occurrence of vocal dysfunction that causes of laryngeal muscle and heard as hoarseness, dysphonia. The most hoarseness. About 1/3 of the total population during certain period common causes of laryngeal paralysis are: 1) goiter of the thyroid of life experiences hoarseness. Control of phoniatric function be- gland 2) thyroid surgery 3) thoracic surgery 4) neurological caus- gins on the cerebral cortex, depends upon respiratory musculature, Most common etiologies of neurogenic laryngeal paralysis in middle-aged patients 121 the state of the lungs and expiratory air flow through the trachea and Etiology of laryngeal paralysis was demonstrated in 99 patients, larynx and the vocal cords, and also depends of n. recurrensa function while the remaining 11 patients were classified as idiopathic larynge- innervated by opening and closing of the glottis (7-12). al paralysis. Among the most common causes of vocal paralysis are neck The age group that was involved in the study included the pa- and chest injuries, goiter, thyroid tumors, cancers of the esopha- tients between 25 and 83 years of age and it appeared that the pa- gus and lung, as well as complications after their surgery. Causes of ralysis of the vocal cords larynx was predominantly found in the neurogenic laryngeal paralysis can also be metastasis in the lymph middle-aged patients, as shown in Table 1. nodes as well as aortic aneurysm, viral infections, prolonged intuba- Table 1 Age distribution. tion and idiopathic neurogenic paralysis (cases where etiologic origin Frequency factor has not been determined). The main symptoms of unilateral Age rate (one-sided) paralysis of the larynx are hoarseness/dysphonia and Absolute Relative difficulty in swallowing/dysphagia, while in bilateral paralysis more 26 -35 7 6.36% pronounced are breathing disturbances (dyspnea) due to narrowing of the airway caused by the vocal cords position. Position of the 36 - 45 15 13.63% vocal cords determines the degree of glottal occlusion, which affects 46 - 55 14 12.72% the respiratory function and the degree of hoarseness (10,11,12). The aim of this article is to determine the prevalence and etio- 56 - 65 32 29.09% logical factors and symptoms of unilateral and bilateral neurogenic 66 - 75 26 23.63% paralysis of the larynx (gender, age) and their differences. 76 - 85 16 14.54% MATERIALS AND METHODS Total 110 100%

We performed a three-year prospective study, which included Bilateral paralysis of the vocal cords was found in 18 patients, 110 patients an Ear, Nose and Troath Clinic, Clinical Center of Ban- predominantly in women - 16 patients (88.8%), as shown in Figure 2. ja Luka, who were monitored through phoniatric examination. The data were analyzed by using standard statistical methods. The differ- ences between the groups were compared by using the χ2 contigen- cy test. For the purpose of comparison of the average values of pa- rameters, we used the Student test for independent samples and non-parameter Mann-Whitney test (the values with p<0,05 were taken as statistically significant). For the purpose of determining the degree of the observed parameters correlation, we applied the Pearson parameter correla- tion. All results are presented in the tables and figures below.

RESULTS

Figure 2 Gender distribution of bilateral paralysis. The total number of patients included in this study was 110, of which 70.9% were females and 29.9% males. In our study, we have Complications after surgery of the thyroid gland were leading found that 83.64% were unilateral neurogenic vocal cord paralysis, etiologic factor in the development of bilateral neurogenic laryngeal against 16.36% of bilateral paralysis, as shown in Figure 1. paralysis, as shown in Figure 3.

Figure 1 Localization of the involvement of the vocal cords. Figure 3 Etiology of bilateral paralysis.

122 M. Gnjatić et al.

Based on the statistical data processing, we noticed that there DISCUSSION was a statistically significant difference among the etiological causes of disease (p<0.01). Based on the results, we found out that the occurrence of uni- lateral neurogenic paralysis was more common on the left than on the right side. Left-sides paralyses were observed in 49 patients (53%), compared to 43 right-sided paralyses. We observed numer- ous etiological factors for the development of unilateral paralysis of the larynx in a group of patients with known etiology of the disease. Unilateral paralyses, according to the gender distribution, were twice as often in women than in men. The damages to the left n.laryngeusa reccurensa are far worse and much more frequent than damage to the right n. laringeusa rec- curensa, as shown in the results of our work, where we obtained statistically significant more frequent incidence of left-sided paral- ysis. In most cases we were able to clearly determine the etiologic cause of the paralysis. However, the cause of unilateral neurogenic paralysis has not been determined in 19 patients. Determined etio- Figure 4 Gender distribution of unilateral paralysis. logical cause of unilateral neurogenic laryngeal paralysis was statisti- Unilateral neurogenic paralysis occurs much more frequently in cally more common than idiopathic cause of this disease. Exploring women (62/30), as shown in Figure 4, rather than in men. There- the causes of neurogenic paralysis of the larynx, we concluded that fore, the difference in the gender distribution is highly significant surgeries on the thyroid was the most common cause of the dis- (p<0.01). ease. This can be interpreted by consequences that initially led to the primary disease (for example, infiltration of nerves by malignant Table 2 Distribution of etiological factors of unilateral la- thyroid tumors, as well as compromised nerves vascularization due ryngeal paralysis. to physical pressure of the present tumor), hence the risks of surgi- cal intervention in the thyroid gland and the possibility of intraoper- Etiology of

unilateral Frequency % ative injuries to the corresponding neural structures. paral ysis Our study has shown that surgery of the thyroid gland is the Thyroid surgery 27 29.35 leading etiologic factor in the development of neurogenic paralysis.

Thyroid goiter 15 16.30 In our patients it was present in 35.45% of cases as an etiological

Idiopathic 11 11.96 factor, followed by goiter of the thyroid gland in 14.55%, idiopathic paralysis in 10% of cases, which is consistent with the studies de- Vir al infection 8 8.70

Diabetes 7 7.61 veloped by other authors from the region (13, 14, 15, 16, 17, 18, Post operative 19). thyroid cancer 4 4.35 Development of the thyroid surgery has drawn attention to the Thoracic surgery 5 5.43 possibility of neurological disturbance on larynx, which frequently Prolonged follows this type of surgery. According to the research of various 5 5.43 intubation authors, such are Tucker HM (1986), Denis D,and Kasshimae H. Lung cancer 3 3.26 (1989) and many other later on, the increase in the number of pa- Esophageal tients with bilateral larynx paralyses continues. carcinoma 2 2.17

Thyroid A group of American authors dealing with similar issues within carcinoma 0 0.00 the States, where the data point to neck and cervical spine injuries, CVI (n eurologic) 1 1.09 mostly occurred in traffic accidents, as one of the leading etiological Chondrosarcoma 1 1.09 factors in the development of neurogenic paralysis, in 1.27 – 2.7% Diabetes 7 7.61 of the cases, thyroid surgery 2.1%, heart surgery 1.4%, esophageal Miocardiopathy 1 1.09 carcinoma 1.3%, prolonged intubation 1.8% (data from 2009). Resection of In the cases where we were unable to determine the etiology trachea 0 0.00 of neurogenic paralysis, we assumed its etiological cause could be a Total 92 100.00 neurotropic virus or an allergic toxic mechanism.

CONCLUSIONS Carcinoma of the lung, specifically thorax surgery, led to the disease in 12 (13%) patients. In patients included in our study some Our research resulted in a conclusion that the leading factor in less common causes of neurogenic unilateral laryngeal paralysis the development of life-threatening bilateral paralysis, and the most were observed, such as: thoracic surgery (5.43%), neurological common reason, is thyroid gland surgery, increasing due to the ma- causes (2.1%), prolonged intubation (5.43%), esophageal carcinoma lignant disease growth, as well as the operation risks. Our study has 2 (2.1%), and insulin-dependent diabetes mellitus (7.61%), Table 2. shown that the complications of the thyroid gland surgery are the Most common etiologies of neurogenic laryngeal paralysis in middle-aged patients 123 leading etiological factor in the neurogenic laryngeal paralysis devel- 12. Sapundzhiev N, Lichtenberger G, Eckel HE, Friedrich G, Zenev I, Toohill RJ, et al. opment. The frequency of neurogenic unilateral larynx paralysis is Surgery of adult bilateral vocal fold paralysis in adduction: history and trends. Eur highly significant in relation to the cause of paralysis. This significant Arch Otorhinolaryngol. 2008 Dec;265(12):1501-14. Epub 2008 Apr 17. 13. Hung CC, Lee JC, Hsiao LC, Lin YS. Vocal cord immobility caused by the difference is caused by a large number of resulting paralyses follow- long-standing impaction of a fishbone in the hypopharynx. Laryngoscope. 2009 ing the thyroid surgery. Jan;119(1):228-30. 14. Roh JL, Yoon YH, Park CI. Recurrent laryngeal nerve paralysis in patients with papil- Conflict of interest: none declared. lary thyroid carcinomas: evaluation and management of resulting vocal dysfunction. Am J Surg. 2009 Apr;197(4):459-65. Epub 2008 Oct 11. REFERENCES 15. Sylva M, van der Kooi AJ, Grolman W. Dyspnoea due to vocal fold abduction paresis in anti-MuSK myasthenia gravis. J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1083-4. 1. Đukić BV. Komparativna studija klasične laserske hirurgije u restauraciji larinksnih 16. Sancho JJ, Pascual-Damieta M, Pereira JA, Carrera MJ, Fontané J, Sitges-Serra A. funkcija kod obostranih paraliza glasnica. Doktorska disertacija. Univerzitet u Beo- Risk factors for transient vocal cord palsy after thyroidectomy. Br J Surg. 2008 gradu, Medicinski fakultet, 1994 Aug;95(8):961-7. 2. Đukić BV, Stanković P, Klinička anatomija i fiziologija. Otorinolaringologija i maksilofaci- 17. Yeung P, Erskine C, Mathwes P, Crowe PJ. Voice changes and thyroid surgery: is pre jalna hirurgija. Beograd, Univerzitet u Beogradu, Medicinski fakultet, 2004, 142-147 operative indirect laryngoscopy necessary? Aust N Z J Surg 1999 Sept;69(9):632-4 3. Stanković P, Klinička Analiza jednostranih neurogenih paraliza larinksa primenom 18. Moulton-Barret R, Crumley R, Jalile S, Segina D, Allison G, Marshak D, et al Com- neinvazivnih dijagnositčkih i terapijskih metoda, Univerzitet u Beogradu, Medicinski plications of thyroid surgery. Int Surg 1997Jan-Mar;82(1):63-6. fakultet, Beograd 1994, 5-42 19. Bellantone R, Boscherini M, Lombardi CP, Bossola M, Rubino F, De Crea C, et al. 4. Marinković S, Milisavljević M, Kostić V. Funkcionalna i topografska neuroanatomija, Is the identification of the external branch of the superior laryngeal nerve manda- Naučna knjiga Beograd, 1989,2:10-12 tory in thyroid operation? Results of a prospective randomized study. Surgey 2001 5. Yumoto E, Minoda R, Hyodo M, Yamagata T. Causes of recurrent laryngeal paraly- Dec;130(6): 1005-9 sis. Auris Nasus Larynx, 2002 Jan;29(1):41-5. 6. Rubin AD, Sataloff RT, Vocal fold paresis and paralysis: what the tyroid surgeon should know. Surg Oncol Clin N Am. 2008 Jan; 17(1):175-96. 7. Polednak AP. Vocal fold palsy after surgery in elderly thyroid cancer patients with versus without comorbid diabetes. Surgery. 2009 Jun; 145(6):685-6. Epub 2009 Apr 11. 8. Sittel C, Bosch N, Plinkert PK. Surgical voice rehabilitation in unilateral vocal fold Reprint requests and correspondence: paralysis. Chirurg. 2008 Nov;79(11):1055-64. Mirjana Gnjatić, MD, PhD 9. Sulica L. The natural history of idiopathic unilateral vocal fold paralysis: evidence Clinic of ENT and problems. Laryngoscope. 2008 Jul; 118(7):1303-7. Clinical Centar Banja Luka 10. Wang CC, Chang MH, Wang CP, Liu SA. Prognostic indicators of unilateral vocal 12 beba 1 fold paralysis. Arch Otolaryngol Head Neck Surg. 2008 Apr;134(4):380-8. 78000 Banja Luka, RS 11. Omland T, Brøndbo K. Paradoxical vocal cord movement in newborn and congen- Bosnia and Herzegovina ital idiopathic vocal cord paralysis: two of a kind? Eur Arch Otorhinolaryngol. 2008 Phone: +387 65 541 777 Jul; 265(7):803-7. Epub 2008 Apr 18. Email: [email protected]

Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Medical Journal (2014) Vol. 20, No. 2, 124 - 126 Professional article Surgery and endoscopic treatment in children with vesicoureteral reflux Operativni i endoskopski tretman djece sa vezikoureteralnim refluksom

Murat Berisha*, Nexhmi Hyseni, Salih Grajqevci, Sejdi Statovci, Ali Aliu

Pediatric Surgery Clinic, University Clinical Center, Prishtina, Kosovo

*Corresponding author

ABSTRACT SAŽETAK

Introduction: vesicoureteral reflux (VUR) is a pathologic entity with Uvod: vezikoureteralni refluks (VUR) je patološka jedinica sa different forms of therapeutic management. The aim of this study is to različitim vrstama terapijskih zahvata.Cilj ove studije je da se uporedi compare and analyze surgical and endoscopic treatment of children i analizira operativni i endoskopski tretman djece sa VUR-om (od II do with VUR (from grade II to IV). Also, medical charts of children with IV stepena). Također, izvršit će se analiza liječničkih grafikona djece sa VUR will be analyzed with special focus on results of endoscopic sur- VUR-om sa fokusom na rezultatima endoskopskih zahvata. Metode: u gery. Methods: from 2000 to 2013, 44 children with RVU (61 urethers) periodu od 2000. do 2013. godine, 44 djece sa RVU (61 ureter) je liječeno were surgically treated. Endoscopic surgery in our Center has started operativnim zahvatom. U našem Centru endoskopski zahvati počeli su se in 2009. In the period 2009-2013, 55 children with RVU were treated primjenjivati u 2009. godini. U periodu od 2009. do 2013. godine, 55 djece with endoscopic surgery (78 urethers). Three months postoperatively sa RVU-om je liječeno primjenom endoskopskog zahvata (78 uretera). Tri avoiding cystourethrogram (VCUG) was performed. Results: 44 pa- mjeseca nakon zahvata urađen je cystourethrogram (VCUG). Rezultati: 44 tients were surgically treated (ureterocystoneostomia sec.Cohen) and pacijenta podvrgnuta su hirurškom zahvatu (ureterocystoneostomia sec. average hospitalisation was 6 days. The average age of patients was 6.5 Cohen) i njihova hospitalizacija je trajala u prosjeku 6 dana. Pacijenti su u years. In 7 cases (15.9%) we had postoperative complications. 55 pa- prosjeku imali 6.5 godina. U 7 slučajeva (15.9%) došlo je do postoperativnih tients were treated with endoscopic surgery, and average hospitalisa- komplikacija. 55 pacijenata je tretirano primjenom endoskopskog zahvata, tion was 1 day. In 6 patients (6.6%) endoscopic surgery with deflux was i hospitalizacija ovih pacijenata trajala je u prosjeku 1 dan. Kod 6 pacijenata done twice, while in three patients (8.5%) it was done 3 times, because (6.6%) endoskopski zahvat sa defluksom je obavljen dva puta, dok je taj of recurrence. The average age of those patients was 5.2 years. Con- zahvat kod tri pacijenta (8.5%) obavljen 3 puta, zbog vraćanja bolesti. clusion: the endoscopic surgery of the VUR is much easier for both the Prosječna starosna dob tih pacijenata je bila 5.2 godine. Zaključak: pediatric surgeon and the patient. We suggest that endoscopic surgery endoskopska metoda tretiranja VUR-a je mnogo lakša i za hirurga i za should be offered to all children with grade II to IV VUR. We strongly pacijenta. Predlažemo da bi se sva djeca kod kojih je dijagnosticiran od recommend the endoscopic surgery to the majority of VUR cases that II do IV stepena VUR-a trebala podvrgnuti endoskopskom zahvatu. come to our Center. Zalažemo se za to da se većini pacijenata sa dijagnosticiranim VUR-om koji dođu u naš Centar predloži endoskopski zahvat, kao metod liječenja.

Key words: vesicoureteral reflux, pediatric urology Ključne riječi: vezikoureteralni refluks, pedijatrijska urologija

INTRODUCTION of symptomatic urinary tract infection (UTI) varies between 30% and 50% in different publications (6). Bilateral reflux resolves at a Vesicoureteral reflux (VUR) is a common problem encoun- slower ratethan unilateral reflux (7). In 1952, Hutch, carried out the tered in urological practice. Traditionally, if medical management first re-implantation of ureter in humans (8). In last ten years, since with low-dose antibiotic prophylaxis failed, the only alternative was Deflux (dextranomer hyaluronic acid copolymer) was approved by open surgery. Recently, promising results with subureteral injection the Food and Drug Administration (FDA), endoscopic surgery is the of dextranomer/hyaluronic acid copolymer (Deflux) have renewed first treatment of children with RVU (9). interest in the endoscopic treatment of VUR (1). Endoscopic treat- ment (ET) was pioneered by O’Donnell and P. Puri when they pre- MATERIALS AND METHODS sented their first report in 1982(2). ET of VUR in children has now become an acceptable alternative to open ureteral re-implantation This study includes children treated for RVU and the data were for the treatment of pediatric VUR (3). In humans, one method for obtained from histories of patients of our center. The surgical treat- assessing VUR is avoiding cystourethrogram (VCUG), in which a ment of children with RVU in our center started since 1999. We catheterized bladder is filled with radiopaque contrast under fluo- are the only center in the country that treats RVU in children. The roscopy (4). Early diagnosis is very important to reduce and prevent diagnosis of these children was correct and was found out through complications (5). The prevalence of VUR in children with a history physical, laboratory and radiological examinations. Radiological Surgery and endoscopic treatment in children with vesicoureteral reflux 125 examinations used to verify the diagnosis were as follows: ultra- as follows: long stay in hospital, postoperative pain, limited move- sonography, voiding cystourethrogram (VCUG), and radionuclide ments, whereas a characteristic of endoscopic surgery was as fol- cystogram (RNC). The RVU treatment with open surgery consists lows: short stay in hospital, no postoperative pain, no limited move- of re-implanting of the ureter with a reflux. Whereas the RVU treat- ments. In our center, the success rate of children with RVU that ment with endoscopic surgery is carried out by injecting, through were treated with endoscopic surgery was 83.6% and this shows cystoscopy, Deflux in the subureteral part (sub-mucosa) of ureter that the success rate in case of our patients is similar to the one of that has a reflux (10). other centers, referring to some studies such as Pinto et al. (13) that reported the success rate of 84%, while Puri et al. (14) reported RESULTS success rate of 96%. Capozza et al. have shown that non-function- ing of bladder (neurogenic bladder) is a risk factor for the failure From 1999 to 2013, 99 children were treated. Following the op- of endoscopic surgery (15). Therefore, our Center does not even eration, children were observed for approximately 24 months. Until think of endoscopic surgery in cases of children with neurogenic 2009 all children with RVU were treated by open surgery (ureter bladder and RVU. Children treated with the RVU in our Center are re-implantation). Since 2009, our center has started treating the pa- observed for 2 years, whereas according to Chertin et al., minimum thology in question with endoscopic surgery (Deflux injection). 44 observation time of these children should be 3 years (9). In general, patients were treated with open surgery (61 ureters) whereas 55 the reported rate of big complications caused by endoscopic sur- children were treated with endoscopic surgery (78 ureters). There gery is too low and is favored in parallel to open surgery (16). were complications in relation to treating the RVU with open sur- gery. 7 children (15.9%) with RVU treated with open surgery suf- CONCLUSION fered postoperative complications. On the other hand, there were no complications in cases with endoscopic treatment, apart from The treatment of children with RVU with open surgery and en- some repeated treatments. The first treatment with endoscopic sur- doscopic surgery is successful in our center. Endoscopic surgery is gery was successful in 46 children (83.4%). In order to cure them easier and more feasible for pediatric surgeons and patients. Endo- from RVU, 6 children (16.6%) had to undergo endoscopic treatment scopic surgery has more advantages than open surgery. The advan- twice whereas 3 children (8.5%) underwent the treatment three tages of endoscopic surgery are: short hospital stay, absent of post- times (Figure 1). Children treated with open surgery were hospital- operative complications and high success rate. Endoscopic surgery ized for 7 days, received parenteral therapy, had a urinary catheter is preferred as the first line of RVU treatment. and suffered postoperative hematuria. Whereas children treated with endoscopic surgery had no complications, the treatment was Conflict of interest: none declared. repeated in some cases, they were hospitalized for one day, received per os therapy, no hematuria, no urinary catheter. When it comes to REFERENCES open surgery, the average duration of intervention was 180 minutes and average stay in hospital was 6 days, whereas in case of endo- 1. Guerra LA, Khanna P, Levasseur M, Pike JG, Leonard MP. Endoscopic treatment of scopic surgery the average duration of intervention was 25 minutes vesicoureteric reflux with Deflux: a Canadian experience. Can UrolAssoc J. 2007 and only one day stay in the hospital. There was a huge difference of Mar;1(1): 41-5. RVU treatment with open surgery and endoscopic surgery, but they 2. O’Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of were both successful. Teflon. Br Med J 1984 Jul;289:7-9. 3. Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS,et al. Pedi- atricvesicoureteric reflux. Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997 May; 157(5):1846-51. 4. Rossleigh MA. Renal infection and vesico-ureteric reflux. Semin Nucl Med 2007 Jul;37(4):261–8. 5. Lee HY, Soh BH, Hong CH, Kim MJ, Han SW. The efficacy of ultrasound and- dimercaptosuccinic acid scan in predicting vesicoureteral reflux in children below theage of 2 years with their first febrile urinary tract infection. PediatrNephrol.2009 Oct;24(10):2009-13. 6. Olbing H, Hirche H, Koskimies O, Lax H, Seppänen U, Smellie JM. Renal Growth in Children with Severe Vesicoureteral Reflux: 10-year Prospective Study of Medical Figure 1 Outcome of endoscopic correction of VUR. and Surgical Treatment. Radiology 2000 Sep;216(3):731-7. 7. GreenbaumLA, Mesrobian HG. Vesicoureteral Reflux. PediatrClin North Am. 2006 DISCUSSION Jun;53(3): 413-27. 8. Baek M, Kim KD. Current Surgical Management of Vesicoureteral Reflux.Korean J In a survey of parents whose children suffered from VUR, 95% Urol. 2013 Nov;54(11):732-7. of them said they preferred endoscopic surgery, compared to 5% 9. Chertin B, Kocherov S, Chertin L. Natsheh A, Farkas A, Shenfeld OZ, et al. En- who were in favor of open surgery. This was also expressed by doscopic Bulking Materials for the Treatment of Vesicoureteral Reflux: A Re- view of Our 20 Years of Experience and Review of the Literature. Adv Urology. Capozza et al. in their study of 2003 (11). The biggest difference of 2011;2011:309626, doi:10.1155/2011/309626. endoscopic surgery is minimal postoperative pain and quick heal- 10. Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M., Caione P. Treatment of ing (12). The study presents huge differences of these methods for vesico-ureteric reflux: a new algorithm based on parental preference. BJU Int. 2003 treatment of RVU in children. A characteristic of open surgery was Aug; 92(3):285-8. 126 M. Berisha et al.

11. Ortenberg J. Endoscopic treatment of vesicoureteral reflux in children.UrolClin- North Am. 1998 Feb25(1)151-6. 12. Pinto KJ, Pugach J, Saalfield J. Lack of usefulness of positioned instillation of contrast cystogram after injection of dextranomer / hyaluronic acid. JUrol 2006 Dec;176(6 Pt 1):2654–6. Reprint requests and correspondence: 13. Puri P, Pirker M, Mohanan N, Dawrant M, Dass L, Colhoun E. Subureteraldex- Murat Berisha, MD, MSc tranomer/hyaluronic acid injection as first line treatment in the management of Clinic of Pediatric Surgery high grade vesicoureteral reflux. J Urol. 2006 Oct;176 (4 Pt 2):1856–9; discussion University Clinical Center 1859-60. St. Rexhep Krasniqi 14. Capozza N, Nappo S, De Gennaro M, et al: Dysfunctional voiding as a cause of Kulla III-k-II-5 failure of endoscopic treatment of vesico-ureteral reflux. ICCS. 3rd International Prishtina Children’s Continence Symposium. 1995. 117-120. Kosovo 15. Wang TM, Chen HW, Chu SH. Recent Advances in the Endoscopic Treatment of Phone: +381 44 116 512 Vesicoureteral Reflux. JTUA 2008;19:1-4. Email: [email protected]

Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini! Medical Journal (2014) Vol. 20, No. 2, 127 - 129 Professional article Blood pressure oscilation during carotid endarterectomy in superficial cervical plexus block Oscilacije krvnog pritiska tokom karotidne endarterektomije u superficijalnom bloku cervikalnog pleksusa

Dragan Milošević*, Darko Golić

Clinic of Anesthesia and Intensive Care, Clinical Center Banja Luka, Zdrave Korde 1, 78000 Banja Luka, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Carotid endarterectomy (CEA) is a surgical procedure per- Karotidna endarterektomija (CEA) je hirurška procedura čijim formed to remove deposits of fat, called plaque, from the carotid izvođenjem se uklanja plak iz karotidnih arterija vrata. Dvije glavne arteries in the neck. Two main arteries, one on each side of the karotidne arterije, svaka sa po jedne strane vrata dopremaju krv i neck, deliver blood and oxygen to the brain. Plaque occurs in sub- kiseonik do mozga. Plak se stvara na intimi velikih i srednjih arterija intimal layer in large and medium arteries as people get older, de- u poznijim godinama u zavisnosti od životnih navika i hereditarnih pending on the lifestyle and hereditary facors. The plaque build up faktora. Tako nastaje vaskularno oboljenje nazvano ateroskleroza. is a vascular disease called atherosclerosis. When this happens, the Njenim razvojem lumen arterija se sužava i dolazi do stenoze. arteries narrow and that condition is called stenosis. During carotid Tokom karotidne endarterektomije uklanja se plak, ispravlja endarterectomy, a surgeon removes the plaque, corrects narowing, stenoze te omogućuje normalan protok krvi odnosno kiseonika and allows normal flow of blood and oxygen to brain. The goal of do mozga. Cilj ovog rada je ispitivanje hemodinamske stabilnosti our work was examination of hemodynamic stability and oscillation pacijenta i oscilacija krvnog pritiska za vrijeme operativnog of blood pressure during operation procedure. zahvata.

Key words: blood pressure, cervical plexus block, carotid endar- Ključne riječi: krvni pritisak, blok cervikalnog pleksusa, karotidna terectomy endarterektomija

INTRODUCTION stroke 46% (23), myocardial infarction 24% (12), arrhythmia 28% (14), chronic bronchitis/asthma 38% (19). Out of total number of The choice of anesthesia for CEA is still disputable (1,2). Tra- patient, 90% of them were smokers and positive family history of ditionally, CEA has been performed in general anesthesia (GA). carotid disease was observed in 36% (18). Thirty four (68%) cas- Surgeons find it less stressful, the operation does not need to be es were with contralateral occlusion. For premedication, midazol- rushed, patient movement is avoided, and there is a theoretical ben- am (3-5 mg) and fentanil (50-100 mcg) were used and lidocain 1,6 efit – reduced cerebral metabolic requirements. However, GA has -1,8% - 20 ml. All patients received oxygen by mask 2-3 lit./min, some disadvantages, major of them is mandatory, additional and and manitol 20% 100-150 ml routine. On average, duration of op- expensive cerebral blood flow monitoring equipment (2,3). When eration procedure was 82 min, and the average duration of ACC CEA is performed in regional anaesthesia, cerebral blood flow mon- clamping was 16 min. Our choice of anesthetic provide approximate itoring is superior (3). Yet, there are certain disadvantages of region- al anesthesia. It proved to be more stressful for both surgeons and patients, patient movement is present, haemodynamic instabillity may occur and airway protection is poor (4).

MATERIALS AND METHODS

Superficial cervical plexus block was performed in fifty patients, all subjected to carotid endarterectomy. Patients fall in categories II or III according to ASA classification. Average age was 63 years. Figure 1 The landmarks and performing of superficial cer- Comorbidity: diabetes mellitus 40% (20), transitor ishemic attack/ vical plexus block. 128 D. Milošević et al.

90 min. analgesia. We performed continuous monitoring of NIBP, • Blood pressure was increased in 40 cases (80%), systolic from oxygen saturation level, heart rate, ECG (II lead), and verbal/motor 10,7% to 40%, diastolic 12.5 to 35%. Average increase was response, especially during clumping and postoperative period. The 16,5%, for systolic, 18% for diastolic, and 9.9% for mean arterial landmark for superficial cervical plexus block performing was pos- pressure. In three cases we detected decrease of blood pres- terior border of m. sternocleidomastoideus, connection point be- sure, systolic up to 23.7%, and diastolic up to 9.1% (Figure 2,3,4). tween top and middle third of line connecting processus mastoideus and midpoint of clavicula. We used redirection needle technique Table 1 Hemodynamic variables in patients under super- – infiltration of anastetic directly, cranial and caudal than puncture ficialHemodynamic cervical variables block. in patients under superficial cervical block site, 0.5 – 1 cm deep under the skin (Figure 1). Condition of collateral branches Poor (N=16; 32.0%) Good (N=34; 68.0%) p* Mean Std. Deviation Mean Std. Deviation RESULTS Preoperative systolic 145.0 14.085 136.6 15.088 0.068 Preoperative 91.4 7.780 84.6 7.024 0.003 diastolic Results are presented statistically by means of values, graphics Preoperative mean 111.3 8.647 104.2 8.611 0 .0 0 9 Clumping systolic 167.3 8.379 152.9 12.717 0 .0 0 0 and tables. The most important were: Clumping diastolic 104.4 11.735 96.8 10.005 0 .0 2 2 • Heart rate was changed in all patients, -12 to + 22% according Clumping mean 122.8 6.605 119.2 13.328 0.312 * t-test for independent to preoperative values, in five cases bradycardia occurred (40/ samples

min) during preparation – glomus caroticum irritation (atropine

i.v. administration). Hemodynamic variability according to collateral circulation

Figure 2 Preoperative blood pressure. shows high correlation between increasing pressure and poor devel- oped contralateral circulation, particularly in cases where we used antihypertensive medication as shown in Table 1 and 2.

Table 2 Hemodynamic variables in patients under super-

ficialHemodynamic cervical variables block, in patientsI.V. antihipertensive under superficial cervical agens block, (urapidil) administered.I.V. antihiper-tensive agens (urapidil) administered

Condition of collateral branches Figure 3 Intraoperative blood pressure increased in 80%, Poor (N=13; 81.25%) Good (N=3; 18.75%) p* Std. during cross clumping phase 72%, antihipertensive drug Mean Mean Std. Deviation Deviation used in 36% (urapidil). Preoperative systolic 145.8 12.449 161.3 25.541 0.130 Preoperative diastolic 91.2 8.019 91.7 5.686 0.919 Preoperative mean 110.4 9.260 119.7 15.308 0.183 Clumping systolic 169.0 6.916 164.0 12.288 0 .0 4 0 Clumping diastolic 105.8 12.683 97.0 3.606 0 .0 6 6 Clumping mean 124.1 6.525 142.7 33.232 0 .0 5 0 Release systolic 158.4 12.332 144.0 20.881 0.128 Release diastolic 101.5 7.644 92.0 6.083 0.065 Release mean 116.5 10.325 117.7 6.807 0.852 Postoperative systolic 158.5 10.658 148.3 14.224 0.178 Postoperative diastolic 101.8 13.596 93.0 6.557 0.304 Figure 4 Postoperative blood pressure. Postoperative mean 118.5 10.548 112.0 12.288 0.367 * t-test for independent samples

DISCUSSION

There is a strong evidence in literature about preservation of physiological protective mechanism in loco-regional anesthesia in carotid endarterectomy (5). Combining NIRS spectrometry and jug- Figure 5 Average values of all pressures in different stages of ular venous oxymerty McCleary demonstrated that preservation of surgery show tendency of blood pressure increase especially in cerebral circulation during cross clumping period of commuis carot- cross-clumping period, and decrease in post clumping period. id artery, depending on reflex increasing blood pressure and heart rate, was not registered in general anesthesia (6). This discovery is supporeted by Wellman who recorded significantly lower incidence of ischemic changes on EEG intraoperatively in regional anesthesia, 6.3% vs 15.7% in general anesthesia (7). Sympatic nervous system reaction, which is suppressed by general anesthetics, is responsible for the blood preassure increase. This suppression is dose depen- dent, so it is possible to preserve this reflex reaction in „light“ gener- al anesthesia as found by Roizen, explaining some cases of increased blood pressure in general anesthesia (8). It seems that some parts of reticular formation in medula (with possible similar zone trought Blood pressure oscilation during carotid endarterectomy in superficial cervical plexus block 129 the brain tissue), especially sensitive on hypoxia and cessation of REFERENCES circulation (cross clumping period), have important role in this reflex response. Preservation of cerebrovascular physiological mechanism 1. McCleary AJ, Maritati G, Gough MJ. Carotid endarterectomy; Local or General during loco-regional anesthesia can prevent occurrence of ischemic anesthesia? Eur J Vasc Surg 2001;22 1-12. damage in endarterectomy. This claim is confirmed by Calvey who 2. Fioriani P, Sbarigia E, Speziale F, Antonini M, Fiorani B, Rizzo L, et al: General an- esthesia versus cervical block and perioperative complications in carotid vascular in his clinical research measured concentration of protein S 100 (glia suregry. Eur J Vasc Endovasc Surg 1997 Jan; 13(1):37-42. cell degradation product) in jugular vein sample, and results were 3. Meliere D, Desgrangers P, Alaire E, Cron J, Berhalad D, D’Audiffret A, et al. Sur- compared with series of psychometrics tests. The results show sig- gery of the internal carotide: locoregional or general anesthesia? Ann Chir. 2000 nificantly higher concentrations of S 100 protein, and worse psycho- Jul;125(6):530-8. metrics capabilities in group of patients with general anesthesia for 4. Carling A, Simonds M. Complications from regional anaesthesia for carotid endar- endarterectomy compared to cervical plexus block group (9). terectomy Br J Anaesth. 2000 Jun;84(6):797-800. In our investigation there was significant increase of blood pres- 5. Stoneham MD, Thompson JP. Arterial pressure managment and Carotid Endarter- ectomy. Br J Anaesth. 2009 Apr; 102(4): 442 – 52. sure especially in cross clumping period as preserved reflex for cere- 6. McCleary AJ, Dearden NM, Dickson DH, Watson A, Gough MJ. The differing ef- bral blood flow maintenance. We tolerated the increase up to 25% fects of regional and general anesthesia on cerebral metabolism during carotid end- from preoperative (baseline) values, because the further increase arterectomy. Eur J Vasc Surg 1996 Aug; 12(2):173-81. would have negative effect on cardiovascular system. 7. Wellman BJ, Loftus CM, Kresowik TF, Todd M, Granner MA. The differences in EEG changes during endarterectomy in local vs general anesthesia. Neurosurgery. 1998 CONCLUSION Oct; 43(4):769-73. 8. Roizen MF. Anesthesia goals for operations to prevent cerebrovascular insufficien- cy. Clinical Neuroanesthesia 2nd Ed. New York: Churchill Livingstone, 103-122. Based on our results, we can conclude that superficial cervical 9. Calvey TAJ, Bollom P, Cruickshakk J. et al. Difference in cognitive function and pro- plexus block is a low cost, simple and reliable kind of anesthesia for tein S100 production after carotid endarterectomy under local or general anesthe- carotid endarterectomy, providing a good hemodynamic stability, sia. Br J Surg. 2000;87:490. and cerebral perfusion monitoring. Using this type of anesthesia, we avoid all potential complications and side effect of general endo- Reprint requests and correspondence: tracheal anesthesia. The reflex increase of blood pressure in cross Dragan Milošević MD, MSc -clamping period was tolerated up to 25% of preoperative values, Clinic of Anesthesia and Intensive Care which is considered useful for cerebral perfusion maintenance via Clinical Center Banja Luka Zdrave Korde 1 collateral blood vessels. 78000 Banja Luka, RS Bosnia and Herzegovina Phone: +387 51 343 238 Conflict of interest: none declared. Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 130 - 131 Case report Uterine anomalies and pregnancy outcome: uterus unicornis cum cornum rudimentarium Ishod trudnoće kod anomalije uterusa: uterus unicornis cum cornum rudimentarium

Lejla Imširija*, Naima Imširija, Mohamad Abou El-Ardat, Fatima Gavrankapetanović

Clinic of Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Congenital uterus anomalies are most often diagnosed during Kongenitalne anomalije uterusa se najčešće dijagnosticiraju to- clinical examination and even more frequently during delivery or kom kliničkog pregleda, a još češće, pri porodu ili instrumentalnom at the end of instrumental termination of pregnancy. A pregnant dovršetku pobačaja. Trudnica iz Sarajeva, rođena 1978. godine woman from Sarajevo, born in 1978, was admitted to the Clinic of primljena je na Klinici za porodiljstvo u 37. sedmici trudnoće. U Obstetrics in 37 weeks of pregnancy. In her previous pregnancy, prethodnoj trudnoći, tokom carskog reza, ustanovljeno je da paci- during a caesarean delivery, the patient was diagnosed with uterus jentica ima uterus unicornis cum cornum rudimentarium. Zbog ove unicornis cum cornum rudimentarium. Due to this anomaly both anomalije u obje trudnoće bila je karlična prezentacija ploda. Adek- pregnancies resulted in breech presentation. Regular obstetric con- vatnim akušerskim nadzorom, praćenjem biometrije ploda i njegove trols and monitoring biometrics of the fetus and its presentation prezentacije, trudnoća se može izvesti do kraja, te se na svijet može could result in full term pregnancy and a mature newborn delivery. donjeti zrelo novorođenče.

Key words: uterine anomaly, caesarean section, breech presentation Ključne riječi: anomalija materice, carski rez, karlična prezentacija

INTRODUCTION (uterus unicornis, semiuterus) or hypoplasia with rudimentary horn (uterus unicornis cum cronu rudimentario); III group is uterus duplex Congenital uterus anomalies and frequency of their occurrence or didelphys, usually with vagina septa or duplex; IV group is bicor- primarily depend on the tested sample and applied diagnostic meth- poreal uterus, which can be total or partial or only uterus arcuatus; V ods. The congenital uterus anomalies are most often diagnosed during group is aplastic uterus (total or partial); VI group relates to a special clinical examination and even more frequently during delivery or at the syndrome of various changes in women reproductive organs (5). Only end of the instrumental termination of pregnancy (1). A large num- a small number of obstetricians, working in large institutions with a ber of congenital anomalies remain undetected. The most important large number of pregnant women and deliveries, is privileged to see methods for diagnosing congenital anomalies are ultra-sound examina- gravid uterus unicornis able to carry out the pregnancy in full term (6). tions, especially at the beginning of pregnancy, hysterosalpingography, and combined laparoscopy and hysteroscopy (2). Nowadays, the ap- CASE REPORT plication of magnetic resonance and three dimensional images result in precise detection of uterus abnormality (3). A pregnant woman from Sarajevo, born in 1978, was admitted to Congenital uterus anomalies mainly occur in partial fusion of the the Clinic of Obstetrics in 37 weeks of pregnancy. Prior to this preg- mullerian ducts or in lack of the fusion. The most common anomalies nancy the patient had one miscarriage and a delivery which resulted in relate to those connected to the uterus body, cervix and vagina anom- cesarean section in 34 weeks of pregnancy due to premature rapture alies are less common, while anomalies of ovary and fallopian tubes of membranes and breech presentation. She gave birth to a baby boy are uncommon (4). The American Society for Reproductive Medicine which was hospitalized at the Pediatric Ward of the Clinic. During the (ASRM) anomaly classification, based on intensity and level of fusion pregnancy the patient was regularly monitored and subjected to regu- or lack of the mullerian ducts fusion, along with the Buttram and Gib- lar obstetric examinations. Prior to a delivery and at the beginning of bons classifications, is the most frequently used classification of the the third trimester she was diagnosed with breech presentation which uterus anomalies (5). Based on Buttram and Gibbons classification remained until delivery. Due to the breech presentation and uterus uterus anomalies are divided into 6 groups. The first group relates to unicornis cum cornum rudimentum diagnosed during the previous agnesis and hypoplasia of any organ; II group involve one-sided aplasia caesarian delivery, the second delivery also ended in caesarian section. Uterine anomalies and pregnancy outcome 131

CONCLUSION

Uterus unicornis cum cornum rudimentarium is a rare uterus anomaly, and occurs in one out of 10,000 pregnant women. If preg- nancy happens, breech presentation delivery occurs in majority of cases. Unfortunately, the anomaly is detected during the surgical completion of delivery, in women giving birth for the first time, or during sterility treatment, when a radiology-diagnostic method is used.

Conflict of interest: none declared.

REFERENCES Figure 1 Uterus during caesarian section (typical example of uterus unicornis). 1. Kupešić S. Okrugli stol o prirođenim anomalijama maternice. Gynaecol Perinatol. 2002;11:42–4. A caesarian section was performed in 37 weeks of gestation. 2. Fedele L, Zamberletti D, Vercellini P, Dorta M, Candiani B. Reproductive perfor- Elective caesarian delivery was performed in general anesthesia. The mance of women with unicornuate uterus. Fertil Steril. 1987 Mar;47(3):416–9. fetus extraction was somewhat difficult due to breech presentation 3. Goldenberg M, Sivian E, Sharabi Z, Mashiach S, Lipitz S, Seidman DS. Reproductive and narrow space in the uterus horn. Hemorrhage was normal for outcome following hysteroscopic management of intrauterine septum and adhe- sions. Hum Reprod. 1995 Oct;10(10):2663–5. this type of surgical intervention and the uterus was sewn up in lay- 4. Williams Obstetrics. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gil- ers. The weight of a delivered baby girl was 2850 grams. After a strap LC (ur.). Stanford: Appleton & Lange, 1993. day spent in the Intensive Care Ward the patient was moved to 5. Buttram VC Jr, Gibons WE. Müllerian anomalies: a proposed classification. Fertil Postnatal Ward and discharged 4 days later. As a result of congenital Steril. 1979 Jul;32(1):40–6. uterus anomaly the patient was under strict control of the obstetri- 6. Ivanišević M, Đelmiš J, Mayer D. Početak i napredovanje poroda. Gynaecol Perina- cians and was subjected to ultrasound and obstetric examinations tol. 2001;11:74–9. and mandatory cervicometry (Figure 1). 7. Škrablin S, Kalafatić D, Goluža T, Zlopaša G, Kuvačić I.Prijevremeni porod. Gynae- col Perinatol. 2001;11:129–37. 8. Radaković B. Urođene anomalije ženskih spolnih organa. U: Šimunić V. i sur. (ur.). Ginekologija. Zagreb: Naklada Ljevak, 2001;91–100. DISCUSSION

Discussion on congenital anomalies with a particular reference to uterus unicornus cum cornu rudimentario, brings up several is- sues such as: outcome of pregnancy, uterus reactivity, and the issue of anomalies causing infertility. Unicornuate uterus is certainly the state of uterus with limited space, resulting in preterm birth and pathological and abnormal presentation of the fetus inside uterus, Reprint requests and correspondence: which in majority of cases ends in caesarian delivery. Number of au- Lejla Imširija-Idrizbegović, MD, MSc thors have described unfavorable outcome of pregnancies in wom- Clinic of Obstetrics en with congenital fetus anomalies (7, 8). Pregnancy in women with Clinical Center University of Sarajevo Patriotske lige 81 unicornuate uterus can be regularly controlled if timely diagnosed, 71000 Sarajevo even before the pregnancy. Regular obstetric controls and monitor- Bosnia and Herzegovina ing biometrics of the fetus and its presentation could result in full Phone: +387 61 190 622 term pregnancy and a mature newborn delivery. Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 132 - 133 Case report Hemorrhagic fever with renal syndrome and coexisting hantavirus pulmonary syndrome Hemoragijska groznica sa bubrežnim sindromom udružena sa hantavirusnim plućnim sindromom Duško Anić*, Emina Vukas, Almira Kadić

Pediatric Clinic, Clinical Centre University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: hantavirus causes hemorrhagic fever with renal Uvod: hantavirus uzrokuje hemoragijsku groznicu sa bubrežnim syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). HPS sindromom (HVBS) ili hantavirus plućni sindrom (HPS). HPS dovodi progression to a life-threatening pulmonary disease and has mor- do teškog oblika plućne bolesti sa mortalitetom od oko 40 -50%. tality rate of approximately 40-50%. To the best of our knowledge, Prema našim saznanjima nema objavljenih pedijatrijskih slučajeva there has no published pediatric case of HFRS with coexisting HPS in HVBS udruženog sa HPS u Bosni i Hercegovini. Cilj: cilj ovog rada Bosnia and Herzegovina. Aims: objective of this paper is to describe je da opiše tretman i ishod HVBS udruženog sa HPS. Metoda: the treatment and outcome of treatment of HFRS with coexisting 11–godišnji dječak je primljen sa naglo nastalim respiratornim HPS. Method: a 11 year old boy presenting with an abrupt respiratory distresom, plućnim edemom i bubrežnim zatajenjem. Po prijemu, distress, pulmonary edema and renal failure. After admission cardio- kardiopulmonalna reanimacija je trajala dva sata. Primio je šest doza pulmonary resuscitation lasted for two hours. Received six doses of adrenalina. Uveden u terapijsku hipotermiju i rađena je hemodijaliza. adrenaline. Introduced in therapeutic hypothermia and hemodialysis. Hantavirus infekcija je dokazana serologijom: ELISA IgG i IgM Hantavirus infection was proven by serology: ELISA positive IgM and pozitivan titar antitjela. Rezultati: dječak je otpušten kući potpuno IgG titers. Results: the boy was discharged home completely recov- oporavljen, bez komplikacija osim blagog neurološkog deficita za ered without complications except mild neurological deficit for which koji neuropedijatri nisu sigurni da je povezan sa bolešću. Zaključak: neuropediatricians was not sure that is a consequence of the disease. primarna reanimacija je bila ključna za pozitivan ishod. U slučajevima Conclusion: the primary resuscitation was a key for good outcome in akutnog bubrežnog zatajenja pojava teškog respiratornog zatajenja case of renal failure with occurrence severe respiratory failure must treba navesti ljekare da misle na hantavirusni plućni sindrom. alert clinician for possible HPS, especially in endemic areas.

Key words: hantavirus, resuscitation, pulmonary syndrome, renal Ključne riječi: hantavirus, reanimacija, plućni sidrom i renalni sin- syndrome drom

INTRODUCTION a weakness in the legs, difficulty in walking, vomiting, diarrhea, and hemorrhagic rash. He had no fever. On the day of admission his Since the first hantavirus was isolated in 1976, at least 22 new symptoms also included tachypnea, tachycardia, no urine output hantaviruses that are pathogenic to humans (1) were isolated, and despite bolus fluids and diuretics, while having a normal blood pres- have the potential to cause two different types of illnesses: hemor- sure. Laboratory findings demonstrated markedly elevated levels of rhagic fever with renal syndrome (HFRS) and hantavirus pulmonary creatinine, N-urea, and metabolic acidosis. The lung X rays pointed syndrome (HPS). Hantavirus pulmonary syndrome (HPS) was first to a significant homogeneous shadowing of the lower two thirds of described in the southwestern region of the United States in 1993 the right lung in addition to a blurry cranial contour in a form of an (2). HPS is a more serious disease than HFRS with a mortality rate infiltrating shadow that extended back all the way to the right-hand of about 40-50% (3). Although, hantavirus infection was known to clavicle. Left paracardially nonhomogeneous shadow demonstrated be endemic to Bosnia and Herzegovina for over 50 years (4), to an infiltrative nature. Because of the need for ventilatory support, our best knowledge there are no published pediatric cases of HFRS the patient was sent to the Pediatric Clinic in Sarajevo. On admission associated with HPS. he was conscious, communicative, disoriented, while having tachy- The aim of this paper is to describe the treatment and outcome pnea (40/min), tachycardia (140/min), cold limbs, BP 132/76 (98) of HFRS associated with an HPS infection of an eleven-year-old boy. mmHg, no fever, bloody urine, hematoma on the left lower leg and a single petechial rush. Laboratory findings on admission: WBC 18.4 CASE REPORT x 109/L, PLT 223 x 109/L, RBC 5.1 x 1012/L, Hb 144 g/L, Hct 0.42 AST 67 U / L, ALT 52 U/L, LDH 453 U/ L, N- urea 35.5 Eleven-year old boy was admitted to the Local Hospital due to mmol/L, creatinine 899 nmol/L, sodium 115, Ca 1.96, albumin 29 an illness that suddenly began five days earlier. The symptoms were g/L, APTT 34.6, INR 1.42 CRP 12.2. X-ray showed pulmonary ede- Hemorrhagic fever with renal syndrome and coexisting hantavirus pulmonary syndrome 133 ma and hemorrhage on both sides (Figure 1). Ultrasound (US) also mechanical ventilation and/or extracorporeal membrane oxygen- demonstrated pleural effusion on both sides. The content of the ation. Mortality rate is approximately 40-50% (9, 10). HPS is rarely thoracic drain tube placed on the right hand side was bright while seen in pediatric population, particularly in Europe (11). According blood-stained. Fresh blood was observed coming from his mouth to the literature data, 95% of HPS cases affect adult patients (12). and nose. Due to the continuing respiratory distress, a child was in- The presented case is the first to be published atypical HFRS case tubated. In the endotracheal tube there was a significant amount of without fever in a pediatric patient in Bosnia and Herzegovina, com- foam and bloody content. Immediately after intubation, the boy ex- bined with clinical presentation of the pulmonary syndrome, and periences a 40/min bradycardia and, cardiopulmonary resuscitation satisfying most of the criteria of the Center for Disease Control and was initiated. The resuscitation lasted for two hours, during which Prevention of Infection Diseases concerning HPS (13). he received six doses of adrenaline. The chest compressions were performed during 1.5 hours. In addition to resuscitation, left tho- CONCLUSION racic drain and central venous catheter were placed. At one point a ventricular fibrillation (VF) occurs but without a need for defibrilla- We believe that the primary resuscitation was essential for the tion. After establishing a normal hearth rhythm, the patient requires positive outcome. In the case of renal failure with occurrence of a continued inotropic support due to hypotension. Therapeutic hy- severe respiratory failure clinician should be alerted for a possible pothermia and hemodialysis were initiated. Control laboratory find- HPS, especially in endemic areas. ings: WBC 17 x 109/L, neutrophils 90.3% with toxic granulation, PLT 285 x 109/L, the content of the thoracic drain WBC 0.190 x Conflict of interest: none declared. 109/L, with 70% lymphocytes, N - urea 35.4 mmol/L, creatinine 850 nmol/L, AST 165 U/L, ALT 79 U/L, CK 264 U/l LDH 654U/l, REFERENCES albumin 20 g/L, APTT not measurable, INR 1.69, lactates 3.1, tro- ponin 1.996 ng/mL, Buny viridae (Hantavirus) antibody WB IgG and 1. Lee HW, Lee PW, Johnson KM. Isolation of the etiologic agent of Korean Hemor- IgM positive, Hantavirus IgG / IgM (ELISA) IgG (8.23) and IgM (7.02) rhagic fever. J Infect Dis. 1978 Mar;137(3):298-308. positive index values, urine protein 3 +, mass of RBC and WBC 20- 2. Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, et al. Hantavirus pulmonary syndrome: A clinical description of 17 patients with a newly recognized 25. Starting with the third day, the urine output improved, although disease. N Engl J Med. 1994 Apr 17;330(14):949-55. the serum creatinine and urea N – continued to be elevated. Ino- 3. Lednicky JA. Hantavirus: a short review. Arch Pathol Lab Med. 2003 Jan; 127(1): 30-5. tropic drugs are excluded and the antihypertensives are introduced 4. Hukić M, Muzaferović S, Tulumović D, Calkić L, Sabović S, Karakas S, et al. Puumala due to elevated blood pressure. On the sixth day the patient was and Dobrava viruses in the northeastern and central regions of Bosnia. Acta Med extubated. Nevertheless, on the same evening, he was again intu- Croatica. 2003;57(5):373-80 bated with signs of pulmonary hemorrhage. On 11th day the boy 5. Bugert JJ, Welzel TM, Zeier M, Darai G. Hantavirus infectio hemorrhagic fever was again extubated, having spontaneous breathing. He continued in the Balkans - Potential nephrological hazards in the Kosovo war. Nephrol Dial Transplant. 1999 Aug; 14(8):1843–4. a gradual recovery. The neuropediatrician observed a very discreet 6. Clement J, Colson P, McKenna P. Hantavirus pulmonary syndrome in New England left-sided hemiparesis, for which he was not certain that it was as- and Europe. N Engl J Med. 1994 Aug 25;331(8):545-6. sociated with the underlying disease and there was no other neuro- 7. Glass GE, Watson AJ, LeDuc JW, Childs JE. Domestic cases of hemorrhagic fever logical defects. He was discharged home, fully recovered, with the with renal syndrome in the United States. Nephron. 1994;68(1):48–51. recommendations that the antihypertensives be gradually phased 8. Khan AS, Khabbaz RF, Armstrong LR, Holman RC, Bauer SP, Graber J, et al. out and an MRI of the CNS be performed. Hantavirus pulmonary syndrome: the first 100 US Cases. J Infect Dis. 1996 Jun;173(6):1297-303 DISCUSSION 9. Bi Z, Pierre Formenty PB, Roth CE. Hantavirus Infection: a review and global up- date. J Infect Dev Ctries. 2008 Feb 1; 2(1):3-23. 10. Terajima M, Hayasaka D, Maeda K, Ennis FA. Immunopathogenesis of hantavirus Hantaviruses, which cause HFRS and HPS, are widely spread in pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD+8+T Evroasia and North America. Hantavirus is transmitted by rodents cells trigger capillary leakage in viral hemorrhagic fevers? Immunol Lett. 2007 Nov to humans in direct contact with infected animals or their secretions, 15;113(2):117–20. such as urine, droppings and saliva. Increased vascular permeability 11. Lednicky JA. Hantavirus: a short review. Arch Pathol Lab Med. 2003 Jan; 127(1): 30-5 plays a major role in the pathogenesis of severe hantavirus infec- 12. Schutt M, Meisel H, Kruger DH, Ulrich R, Dalhoff K, Dodt C. Life-threatening Do- tions. Clinical course is highly variable, and some infected patients brava hantavirus infection with unusually extended pulmonary involvement. Clin Nephrol. 2004 Jul; 62(1): 54-7. are asymptomatic. Clinical manifestations and local distribution of 13. www.cdc.gov/hantavirus/hps the disease depend on the strain of the virus (6,7). HFRS occurs upon infection with Dobrava and Hantaan viruses, while Sin Nom- bre and Andes viruses primarily cause HPS (1,8). HFRS and HPS share some clinical manifestations. Bleeding and kidney failure are Reprint requests and correspondence: the characteristics of HFRS, while pulmonary problems are typical Duško Anić, MD in patients with HPS. With advanced supportive care the mortality Pediatric Clinic Clinical Centre University of Sarajevo rate for patients with severe HFRS is reduced to 0.5%. However, Patriotske lige 81 HPS leads to life-threatening conditions more frequently than HFRS. 71000 Sarajevo After a prodromal phase similar to HFRS, patients with HPS may Bosnia and Herzegovina rapidly develop pulmonary edema and shock, which often requires Email: [email protected] Medical Journal (2014) Vol. 20, No. 2, 134 - 135 Review article Surgical treatment of traumatic flail chest Hirurški tretman traumatskog pokretnog kapka Dušan Janičić¹*, Bojan Gulić¹, Zoran Roljić², Velibor Škrbić³

1Clinic of Thoracic Surgery, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina, ²Clinic of Vascular Surgery, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina, ³Clinic of General and Abdominal Surgery, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina

*Corresponding author

ABSTRACT SAŽETAK

Introduction: traumatic flail chest is movable segment of the Uvod: traumatski pokretni kapak je segment grudnog zida, koji chest wall, which is caused by multiple fractures or by separation nastaje višestrukim prelomom ili separacijom koštanih struktura of ribs rib bones (at least three sequential broken ribs or separated (najmanje tri rebra serijski prelomljena ili odvojena u dvije frakturne into two fracture lines). These injuries are mainly seen in polytrauma linije). Ovakva povreda se najčešće sreće u sklopu politraume. Cilj patients. Our goal is to show the therapeutic benefits of surgical rada je prikazati terapijske prednosti hirurškog tretmana (operativna treatment (operative stabilization) of the flail chest. Materials and stabilizacija) pokretnog kapka. Materijal i metode: retrospektivnom methods: retrospective analysis of the treated patients who under- analizom obrađeni su pacijenti operisani na Klinici za torakalnu hirurgiju went surgery at the Clinic of Thoracic Surgery in Clinical Center KC Banja Luka u periodu od 01.12.1997. – 31.12.2012. Rezultati: u Banja Luka in the period from 01.12.1997 - 31.12.2012. Results: petnaestogodišnjem periodu na Klinici za torakalnu hirurgiju KC thirty five middle age patients with average age of 47.42 years with Banja Luka operativno su tretirana 35 pacijenata sa traumatskim traumatic flail chest were surgicaly treated in the fifteen year peri- pokretnim kapkom srednje životne dobi od 47.42 godine. Prosječno od at the Clinic of Thoracic Surgery Center in Banja Luka. Survival trajanje hospitalizacije je 15 dana. Preživljavanje u grupi operisanih je rate in the operated group was 91.43%. Conclusion: if conservative 91.43%. Zaključak: ukoliko konzervativne mjere kao što su untrašnja measures such as internal stabilization, the use of analgesics, antibi- stabilizacija, primjena analgetika, antibiotika, oksigenoterapija i toaleta otics, oxygen therapy and airway toilet does not lead to stabilization disajnih puteva ne dovedu do stabilizacije disajne funkcije operativno of respiratory function, surgical stabilization of the chest wall is nec- stabilizacija zida grudnog koša je neophodna. essary.

Key words: flail chest, surgical stabilization Ključne riječi: pokretni kapak, operativna stabilizacija

INTRODUCTION MATERIALS AND METHODS

Flail chest is post-traumatic thoracic segment of the wall that Hospital records were processed by using the retrospective does not have continuity with the remaining bony skeleton of the analysis of data on patients treated at the Clinic of Thoracic Sur- chest. It occurs with lost support of at least three ribs in two lines gery, Clinical Center of Banja Luka with traumatic flail chest in the with the trauma (1). Pathophysiological disorder occurs due to the period from 01.01.1997 - 31.12.2012. paradoxical movement: during inspiration flail chest moves toward Both methods described so far: osteosynthesis systems and the inside of the chest, while it moves outward during the expirium. intramedullary stabilization (kischner’s wire and wire stitches) This reduces the efficiency of breathing and the volume of inhaled were used for stabilization of the flail chest. CT scanning was air. This condition is followed by typical clinical triad intrabronhial- performed preoperatively to assess the volume of the thoracic hemorrhage, ineffective cough and anoxia (1.2). trauma. Post-traumatic flail chest is a source of high mortality, especially All surgical treatments were performed under general endo- in polytrauma patients. Early work on the moving flail chest record- tracheal anesthesia, used by double-lumen tube by Karlens. ed a mortality of up to 80% (2). Standard treatment is focused on Posterolateral thoracotomy with exploration of the pleural the treatment of lung parenchymal injury and pain control, often cavity was used as an operational method for the treatment of pa- with the use of mechanical ventilation with positive pressure. Sev- renchymal lung lesions, intrathoracic hemorrhage and intrapleural eral previous studies have shown that there are multiple benefits of clot removal. In the case of laceration of the parenchyma and le- operative, surgical, stabilization of the flail chest (3). sions intrathoracic structures, two intrathoracic drainages were The aim of the work consists in the presentation of therapeutic placed in the front and back line in the fifth and seventh intercostal benefits of surgical treatment (operative stabilization) of flail chest. space. Surgical treatment of traumatic flail chest 135

RESULTS • early extubation of the patient, • complete reduction of the fracture, with perfect anatomical con- Our study covers a fifteen year period from 01.12.1997 to solidation (2,3,4,5). 31.12.2012 during which the Clinic of Thoracic Surgery of CC Banja Most of thoracic surgeons believe that the extensive postero- Luka surgically treated 35 patients with traumatic created flail chest. lateral thoracotomy is the optimal approach, without the need for Surgery was performed on 28 men (80%) and 7 women (20%). Pa- additional thoractic incisions (6). Poor coalesced fractures of ribs in tients’ average age was 47.42 years. In 51.42% (18 patients), the flail chest treated with artificial ventilation, as well as the consequent mechanism of injury was traffic traumatism. Postoperative mortal- pain are additional arguments in favor of the rib fixation (6). ity rate was 8.57%. Causes of mortality associated comorbidity in the elderly and associated polytrauma (abdominal injury, locomo- CONCLUSION tor system, craniocerebral injury). Survival in the operated group was 91.43%. The average length of hospitalization was 15 days. On Flail chest is a serious therapeutic problem which, if not treated twenty patients (57.14%), a suture lung parenchyma was performed appropriately, leads to disturbances in ventilation and gas exchange with the thoracotomy and stabilization of flail chest due to its lac- and ultimately to respiratory failure. If conservative measures such eration. Four patients (11:42%) underwent an extensive resective as the inside stabilization, the use of analgesics, antibiotics, oxygen surgery of lung parenchyma (lobectomy or bilobectomy type). Five therapy and airway toilet does not lead to a stabilization of respi- patients (14:28%) underwent suture hemidiaphragm due to its lac- ratory function, surgical stabilization of the chest wall is necessary. eration. Only two patients (5.71%) underwent a fenestration of Such a relatively simple surgical procedure is far less risky compared pericardium. Three patients (8.57%) were registered with a chronic to the all complications that can arise without it. postoperative pain. Conflict of interest: none declared. DISCUSSION REFERENCES Prolonged artificial ventilation, is still the most commonly used method for the treatment of the unstable segment of the chest wall 1. Leenen I. Special Issue on rib fixation. Eur J Trauma Emerg Surg. 2010 Oct;36(5):405. (2). The goal of surgical stabilization of the unstable chest wall, is to 2. Bemelman M, Poeze M, Blokhuis TJ, Leenen LP. Historic overview of treat- shorten the time of application of respirators and avoid complica- ment techniques for rib fractures and flail chest. Eur J Trauma Emerg Surg. 2010 tions due to his prolonged applications (4). Oct;36(5):407-415. Most studies have shown that surgical stabilization leads to a 3. Bottlang M, Walleser S, Noll M, Honold S, Madey SM, Fitzpatrick D, et al. Biome- chanical rationale and evaluation of an implant system for rib fracture fixation; Eur J reduction in mortality in thoracic trauma, shortens time in the inten- Trauma Emerg Surg. 2010 Oct;36(5):417-426. sive care unit, and reduces the length of application of mechanical 4. Fitzpatrick DC, Denard PJ, Phelan D, Long WB, Madey SM, Bottlang M. Operative ventilation (2,4,5). stabilization of flail chest injuries: review of literature and fixation options. Eur J Indications for use of this surgical procedure are not yet stan- Trauma Emerg Surg. 2010 Oct;36(5):427-433. dardized, but the following are generally accepted by the thoracic 5. Gasparri MG, Tisol WB, Haasler, GB: Rib Stabilization: Lessons Learned. Eur J Trau- surgeons: ma Emerg Surg. 2010;36:435–440 • unstable chest wall if there is an indication for thoracotomy due 6. Billè A, Okiror L, Karenovics W, Routledge T. Experience with titanium devices for rib fixation and coverage of chest wall defects; Interac Cardiovasc Thorac Surg. to intrathoracic injury, 2012 Oct;15(4):588-95. • unstable chest wall without contusion of the lung parenchyma, • paradoxical movement of the unstable segment of the chest wall in patients on a ventilator (PEEP insufficient stabilization), • extensive deformity of the chest wall (4,5). Some authors suggest the following indications: • the existence of strong postoperative pain despite the slight par- adoxical movement, which could lead to respiratory failure, Reprint requests and correspondence: • for associated abdominal injuries, after splenectomy and disposal Dušan Janičić, MD, PhD rifts diaphragm, Clinic of Thoracic Surgery Clinical Center Banja Luka • after exploratory thoracotomy due to penetrating wounds (5). 12 beba 1 Advantages of the surgical procedure are: 78000 Banja Luka, RS • pain reduction, Bosnia and Herzegovina • reduction of the time that a patient spends on a ventilator, Email: [email protected] 136

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140

Novi Evropski vodič za prevenciju tromboembolizma kod A Fib

CHA2DS2-VASc skor za procjenu rizika od tromboembolizma kod A Fib! Risk factor-based point-based scoring system - CHA2DS2 -VASc Risk factor Score Congestive heart failure/LV dysfunction 1 Hypertension 1 Age >75 2 Diabetes mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular disease* 1 Age 65–74 1 Sex category (i.e. female sex) 1 Maximum score 9

*Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates.

Major i non-major riziko fakori za procjenu tromboembolizma kod A Fib! Risk factors for stroke and thrombo-embolism in non-valvular AF Clinically relevant non-major Major risk factors risk factors Previous stroke CHF or moderate to severe LV systolic dysfunction [e.g. LV EF � 40%] TIA or systemic embolism Hypertension Age �75 years Diabetes mellitus Age 65-74 years Female sex

Vascular disease

AF = atrial fibrilation; EF = ejection fraction (as documented by echocardiography, radio nuclide ventriculography, cardiac catheterization, cardiac magnetic resonance imaging, etc.); LV = left venticular; TIA = trasient ischaemic attack.

Algoritam antikoagulantne terapije nakon procjene CHA2DS2VASc i major risk faktora!

Choice of Atrial fibrilation Yes Anti-coagulant Valvular AF* No (i.e. non-valvular AF) Yes <65 years and lone AF (including females) No Assess risk of stroke (CHA DS -VASc score) * Includes rheumatic valvular 2 2 AF, hypertrophic cardiomyopathy, etc. 0 1** �2 ** Antiplatelet therapy with aspirin plus clopidogrel, or - less effectively - aspirin only, Oral anticoagulant therapy may be considered in patients who refuse any OAC Assess bleeding risk (HA S-BLED score) Consider patient values and preferences

No antithrombotic therapy NOAC VKA

NOAC - Novel Oral Anticoagulants, VKA - Vitamin K Antagonists Prijedlog mreže Primarne Perkutane Koronarne Intervencije za Bosnu i Hercegovinu!

Prijedlog mreže Primarne Perkutane Koronarne Intervencije za Federaciju Bosne i Hercegovine!