Medic in Ski Pod Mla Dak 2012

editor in chiefMilo Brankovi

deputy editordr Marko Jankovi

secretaryMilenko Bogdanovi

advisory boardAkademik Prof. dr Neboja LaliProf. dr ivan MaksimoviProf. dr Petar BulatProf. dr Vesna BjegoviProf. dr Slobodan SaviProf. dr Gordana Teofilovski ParapidProf. dr Aleksandra IsakoviProf. dr Marina Svetel

readerProf. Mirjana Gluevi

promoter& ownerMedicinski fakultet, Univerzitet u BeograduDr Subbotia 811000 Beograd, Srbija

coverDr Marko JankoviGNU Free documentation licence, Wikipedia:5q-syndrome bone marrow histology withtypical abnormal megakarycoytes

circulation500 primeraka

editorial boarddr Tina TomaeviMihailo BelaeviMilica ivkoviNeboja Markoviarna Jovanovi

Doc. dr Naa MariDoc. dr Darija KisiDoc. dr Silvio de LukaMilo BrankoviMarko JankoviJelena Lekovi, predsednik CSNIRS-aDarko Radakovi, potpredsednik CSNIRS-a

readerProf. Nataa Mici

E-mail: [email protected].: +381 11 36 36 382Fax.: +381 11 36 36 382ISSN-YU 0369-1527UDK 61 (05)

prepress and pressBeoSing, Beograd

acknowledgementProf. dr Tatjana SimiProf. dr Andreas Engertdr Milo Maksimovidr Milan Marinkovi

Re Dekana Medicinskog fakulteta Univerziteta u Beogradu

Potovani itaoci,

Medicinski podmladak, iji je novi broj sada pred vama, predsta-vlja izuzetnu tekovinu Medicinskog fakulteta Univerziteta u Beo-gradu, koja istovremeno obeleava istoriju Fakulteta, ispunjava njegovu sadanjost i predstavlja nezaobilazni deo njegove uspene budunosti.

Kada se radi o istoriji, to nisu samo 63 godine postojanja ime se mali broj fakulteta moe pohvaliti. Posebnu vrednost predstavlja injenica da su brojni kasnije ugledni nastavnici, saradnici i istra-ivai, kao i potovani lekari, vaan deo svog studentskog doba ugradili u Medicinski podmladak, da se tog vremena sa zadovoljstvom seaju i da to danas sa ponosom istiu.

Kada se radi o sadanjosti, mislim da postoji saglasnost u opredeljenju ka neprekidnom podizanju kriterijuma kvaliteta i kritikom preuzimanje brojnih savremenih kretanja u naunoj publicistici. Ova dva postulata su osnova ouvanja ugleda iz prolosti ali i uspenog opstanka u sve otrijim zahtevima koji se postavljaju u sadanjosti.

Kada se radi o budunosti, uslovi u kojima emo raditi se obino ne boje optimistikim bojama. Meutim, polazei od ostvarenog, asopis ima znaajne potencijale daljeg razvoja. U okviru ovih razvojnih mogunosti vrlo je znaajno intenzivnije ukljuivanje u meunarodne projekte, upravo koristei prednosti jednog savremenog asopisa sa dugom tradicijom.

U celini, sadanja Uprava Fakulteta smatra da je Medicinski podmladak izuzetno vaan deo edu-kacije za nauni rad, kao tradicionalna kola uspenih istraivaa. Zbog toga emo podrati vae inicijative za dalji razvoj asopisa i saraivati u suoavanju sa izazovima kojih e biti na tom putu.

U tom smislu, elim vam svima puno uspeha i zadovoljstva u novoj 2013. godini.

Profesor dr Neboja M. Lali

UVODNA REforeword

Vivere tota vita discendum est ovek ui dok je iv

Potovani itaoci,

ast nam je i zadovoljstvo da vam predstavimo novi 63. dvobroj struno-naunog asopisa Me-dicinski podmladak. S ponosom, podseamo da je re o struno-naunoj publikaciji studenata Medicinskog fakulteta Univerziteta u Beogradu, sa najstarijom tradicijom na balkanskim pro-storima. Odgovorno smo pristupili vanom zadatku koji smo nasledili od naih cenjenih pred-hodnika, da nastavimo sa idejom podsticanja i promovisanja studentskog nauno-istraivakog rada.

Nastojali smo, da odrimo tradiciju objavljivanja najboljih i najinovativnijih studentskih radova koji e predstavljati ne samo kvalitetan akademski materijal za uenje i usavravanje, ve i in-spiraciju za nova istraivanja i dostignua u oblasti medicine. U pripremi ovog dvobroja, teili smo ka ciljevima irim od edukacije i naunog istraivanja, koji se ogledaju u doprinosu na polju linog razvoja svakog mladog lekara u pravcu visoke moralne snage i etikih naela.

elimo da na asopis inspirie nove mlade ljude da krenu putem nauke i istraivanja i da za-jedno sa svojim mentorima, daju svoj doprinos razvoju srpske medicine i pomeraju granice do-stignua u leenju oveka. Da studenti nisu sami na tom putu nauno-istaivakog stvaralatva, govore i editorijali naih nastavnika, prof. dr Neboje J. Jovia, prof. dr Zorana Todorovia, doc. dr Tatjane Terzi i doc. dr Dragane Bogievi, uvaenih strunjaka Medicinskog fakulteta, Univerziteta u Beogradu. Takoe, elimo da se zahvalimo cenjenom profesoru Andreas Engertu sa Univerzitetske Klinike u Kelnu, na ostvarenoj saradnji i editorijalu, koji sa velikom zadovolj-stvom objavljujemo u nasem asopisu.

Nadamo se, da smo uspeli odgovoriti izazovu, da sadraj asopisa bude u istoj meri tematski raznovrstan i zanimljiv kao to je edukativan i nauno referentan. Znanje i usavravanje tokom itavog ivota, jeste put koji je predodreen svima koji su prihvatili ovaj plemeniti poziv i streme ka uspehu.

Na kraju, elimo da se zahvalimo svima koji su svojim radom i angaovanjem doprineli izradi ovog dvobroja asopisa Medicinski podmladak.

S potovanjem,Glavni i odgovorni urednik

Milo Brankovi

Vivere tota vita discendum est ovek ui dok je iv

UVODNA REforeword

SADRAJcontents

foreword

Akademik Prof. dr Neboja Lali, dekan Medicinskog fakulteta, Univerziteta u Beogradu

Milo Brankovi, glavni i odgovorni urednik asopisa Medicinski podmladak

editorials

Hodgkin lymphoma 6Prof. dr Andreas Engert

Ukrteni sindromi modanog stabla 15Prof. dr Neboja J. Jovi

Trovanje antidepresivima 26Prof. dr Zoran Todorovi

Mijeloproliferativne neoplazme 31Doc. dr Tatjana Terzi

Febrilni napadi 36Doc. dr Dragana Bogievi

students papers

Ispitivanje in vitro citotoksinih efekata diazepama na modelu B16 elijske linije melanoma 41Ivana Radulovi

Uticaj risperidona na koncentraciju lipidnih peroksida i aktivnost i ekspresiju superoksid dizmutaze u mozgu pacova perinatalno tretiranih fenciklidinom 48Neboja Markovi

Divertikularna bolest creva na autopsijama 54Sanjin Kovaevi, Davor Kovaevi

Hematoloki parametri, celularnost slezine I tibije starih pacova posle dugotrajnog izlaganja stalnom magnetnom polju 58Darko Radakovi, Rajko Runov, Dejan Radakovi

Uticaj novosintetisanog jedinjenja estarske prirode na diferencijaciju humane promijelocitne leukemijske elijske linije 62eljko Anti

SADRAJcontents

students papers

Efekti toksina vipera ammodytes ammodytes na odabrane bakterijske vrste 68Duan Keki

Metaboliki odgovor na test fizikog optereenja kod fiziki aktivnih i neaktivnih ispitanika 74Rada Jeremi, Ankica Bjeli, Neboja Skorupan

Povezanost odnosa Tg/HDL, insulinske rezistencije i pojave i intenziteta koronarne bolesti u pacijenata sa tipom 2 dijabetesa i nedijabetiara 78Iva Kadi, Lucija Kosi

Fizika aktivnost i bavljenje sportom dece i adolescenata sa epilepsijom 83Mihailo Belaevi, Milo Babi

Oksidativni stres nakon reperfuzionog oteenja izazvanog trombolitikom terapijom kod bolesnika sa modanim udarom 86Bojana Tasi

Procena perioperativnog morbiditeta i mortaliteta kardiohirurkih bolesnika na hroninom programu hemodijalize 92Milan Milojevi

Povezanost metabolikog sindroma i oporavka srane frekvence nakon testa fizikog optereenja 98Nikola Bokovi, Dragoljub Blagojevi

Akutni vertiginozni sindrom kao indikacija za prijem na neuroloko odeljenje 103Marko Beni, Milenko Bogdanovi, Vuk Aleksi

featured article

Pria o insulinu 90 godina od otkria koje je promenilo svet 107Doc. dr Danijela Vuevi, Prof. dr Tatjana Radosavljevi

instructions for the autors

6Medicinski podmladakEditorijali

Decembar 2012Broj 12Izdanje 63

Summary:Hodgkin Lymphoma is the best curable cancer in

adults. With current risk-adapted approaches, 80-90% of patients can be cured long term. The standard of care includes a combination of 2-4 cycles of ABVD in early favorable or early unfavorable stages and additional IFRT. In advanced stages, 6 cycles of BEACOPPescalated or 6-8 cycles of ABVD are being used. High-dose che-motherapy is indicated for relapsing or refractory pa-tients. Currently, there are a number of interesting new approaches for this malignancy including the antibody drug conjugate Brentuximab Vedotin. PET-guided treat-ment approaches might help to further individualize treatment for these patients and, importantly, help to re-duce acute and long-term side effects of treatment.

Introduct ionHodgkin lymphoma (HL) has become one of the best

curable malignancies in oncology. Today, more than 80% of patients can be cured with risk-adapted treatment that in-cludes chemo- and radiotherapy. This progress is mainly due to the development of multi-agent chemotherapy and im-proved radiation techniques. However, there are also severe life-threatening treatment-related side effects including organ toxicity and secondary malignancies. Thus, the treatment ap-proaches must be carefully balanced between optimal disease control and the risk of long-term sequelae. This article gives an overview on the pathogenesis, diagnostic procedures and current treatment approaches for patients with HL.

Pathogenesi sHodgkin lymphoma is divided into the classical vari-

ant (cHL) and nodular lymphocyte predominant HL (NPHL). Classical Hodgkin lymphoma is characterized by the pres-ence of mononucleated Hodgkin and multinucleated Reed/Sternberg (H-RS) cells (figure 1a).

Figure 1a. Classical Hodgkin Lymphoma, Histology. Courtesy of Professor Harald Stein.In contrast, lymphocytic and histiocytic (L&H) cells are pathognomonic for the LPHL subtype (figure 1b).

HODGKIN LYMPHOMA

Prof. dr Andreas Engert

Chairman, German Hodgkin Study Group (GHSG),University Hospital Cologne, Cologne, Germany

7EditorijaliMedicinski podmladak

Izdanje 63Broj 12Decembar 2012

Figure 1b. LPHL and NLPHL, Histology. Courtesy of Francisco Vega-Vazquez, MD, PhD.H-RS cells typically stain strongly positive for CD30 (figure 1c) while L&H cells are CD20-positive and negative for CD30.

Figure 1c. Immunhistology of HL cells, CD30-staining. Courtesy of Professor Harald Stein.

In the majority of cases, H-RS cells are derived from pre-apoptotic germinal-centre B-cells, but have lost most of the B-cell-typical genes. In contrast, L&H cells originate from antigen-selected germinal centre B-cells and are charac-terized by the expression of multiple B-cell markers. H-RS cells are derived from pre-apoptotic germinal center B-cells in most cases, but can also be of T-cell origin. The expression of EBV-latent genes in EBV-positive cases (50%) may play a role in cellular transformation by up-regulating the transcrip-tion factor NF-kB. Many questions on the pathogenesis of Hodgkin lymphoma are still unanswered. Multiple signaling pathways and transcription factors show deregulated activity in H-RS cells that are physiologically not activated in B-cells. These include the NFkB-, Jak-Stat- and PI3k-pathway and signaling molecules such as Notch-1. In addition, the interac-tion of H-RS cells with the surrounding inflammatory cells, the microenvironment, plays an important role in the growth and survival of the malignant cell population.

Epidemiolog yWith an annual incidence of 2-3 per 100000 in Europe

and the USA, HL accounts for approximately 30% of all ma-

lignant lymphoma. Slightly more men than women are af-fected. The onset of disease shows a bimodal distribution among industrialized countries with a first peak in the third decade and a second, smaller peak around 60-70 years of age.

Cl in ica l presentat ionIn Hodgkin lymphoma, swollen lymph nodes of the

cervical or supraclavicular region are initial symptoms in 60-70% patients with; axillary lymph nodes are involved in about 30% of newly diagnosed patients. Almost two-thirds of pa-tients have radiographic evidence of intra-thoracic involve-ment. Bone marrow involvement occurs in less than 10% of newly diagnosed patients. Details on organ involvement at diagnosis are given in table 1.

Table 1. Clinical Involvement of HL

Anatomic site Involvement [%]Waldeyers ring 1-2Cervical nodes 60-70Axillary nodes 30-35Mediastinum 50-60Hilar nodes 15-35Para-aortic nodes 30-40Iliac nodes 15-20Mesenteric nodes 1-4Inguinal nodes 8-15Spleen 30-35Liver 2-6Bone marrow 1-4Total extranodal 10-15

About 40% of patients suffer from B-symptoms, espe-cially those with initial abdominal involvement or advanced stage disease. Other symptoms include pain at the site of nod-al involvement shortly after alcohol consumption, pruritus or fatigue1.

Compared with cHL, nLPHL usually begins as a local-ized, slowly-growing and rather benign disease with involve-ment of only one peripheral nodal region.

8Medicinski podmladakEditorijali


Table 2. Staging Classification for Hodgkin Lymphoma

STAGE Description

I Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyers ring) or involve-ment of a single extralymphatic site (IE).

II

Involvement of two or more lymph node regions on the same side of the diaphragm (hilar nodes, when involved on both sides, constitute stage II disease); localized contiguous involvement of only one extranodal organ or site and lymph node region(s) on the same side of the diaphragm (IIE). The number of anatomic regions involved should be indicated by a subscript (e.g., II3).

IIIInvolvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by in-volvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ site (IIIE) or both (III SE).

III1 With or without involvement of splenic, hilar, celiac, or portal nodes.III2 With involvement of para-aortic, iliac, and mesenteric nodes.

IV Diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without associated lymph node involvement.DESIGNATIONS APPLICABLE TO ANY DISEASE STAGE

A No symptoms.

B Fever (temperature, >38oC), drenching night sweats, unexplained loss of >10% body weight within the preceding 6 months.

X Bulky disease (a widening of the mediastinum by more than one-third or the presence of a nodal mass with a maximal dimension >10 cm).

E Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.CS Clinical stage.PS Pathologic stage (as determined by laparotomy).

Diagnost ics , s tag ing and r i sk st rat i f icat ionAn excisional biopsy of a suspicious lymph node is in-

dispensable for the diagnosis of Hodgkin lymphoma. HL pa-tients are treated according to stage and risk factors. The his-tological subtype except NLPHL does not influence the treatment decision. Stage of disease is classified according to the Cotswolds definition, a modified version of the Ann-Arbor classification (table 2).

The clinical staging is based on CT-scans of the neck, thorax, abdomen and pelvis, and often includes chest X-ray, abdominal sonography, bone marrow biopsy and bone mar-row or skeletal radionuclide imaging. In some cases, addition-al tests such as MRI, PET or liver biopsy might be needed.

The prognostic factors used by the German Hodgkin Lymphoma Study Group (GHSG) for risk stratification of HL

patients is based on stage, B-symptoms, bulky disease of me-diastinal lymphoma manifestation defined as > mediastinal diameter, extranodal manifestation, at least three involved nodal areas and an elevated erythrocyte sedimentation rate. In North America, most centers treat patients according to their traditional classification of early stages (CS I-IIA or B) and advanced stages (CS III-IVA or B, CS I-II A or B with bulky disease defined as >10cm maximum dimension of nodal mass). European study groups such as the EORTC (European Organisation for Research and Treatment of Cancer), GELA (Groupe dEtudes des Lymphomes de lAdulte), and GHSG classify patients into early favorable, early unfavorable and ad-vanced stages depending on the clinical factors listed in table 3.

Table 3. Definition of Treatment Groups by different Study Groups

Treatment Group EORTC/GELA GHSG NCIC/ECOGEarly-stage favorable CS I-II without risk factors

(supradiaphragmatic)CS I-II without risk factors Standard risk group: favorable CS I-II

(without risk factors)Early-stage unfavor-able (intermediate)

CS I-II with 1 risk factors (supradiaphragmatic)

CS I, CSIIA 1 risk factors; CS IIB with C/D but without A/B

Standard risk group: unfavorableCS I-II (at least one risk factor)

Advanced stage CS III-IV CS IIB with A/B; High-risk group:CS III-IV CS I or II with bulky disease; intra-

abdominal disease; CS III, IVRisk factors A large mediastinal mass

B age 50 yearsC elevated ESRD 4 involved regions

A large mediastinal massB extranodal diseaseC elevated ESRD 3 involved areas

A 40 yearsB not NLPHL or NS histologyC ESR 50 mm/hD 4 involved nodal regions

EORTC, European Organization for Research and treatment of Cancer; GELA, Groupe dEtude des Lymphomes de lAdulte; GHSG, German Hodgkin Lymphoma Study Group; ECOG, Eastern Cooperative Oncology Group; NCIC, National Cancer Institute of Canada; CS, clinical stage; NLPHL, nodular lymphocyte predominance Hodgkin lymphoma, NS, nodular sclero-sis; ESR, erythrocyte sedimentation rate (50 mm/h without or 30 mm/h with B symptoms).

9EditorijaliMedicinski podmladak


In order to more precisely define the risk of patients with advanced disease, the International Prognostic Score (IPS) was developed2. The IPS consists of seven risk factors that are associated with a more unfavorable prognosis includ-ing serum albumin 15.000/mm, lymphocytopenia 15.000/mm3 and lymphopenia < 600/mm3 or 8% of white blood cell count. (Hasenclever D et al, N Engl J Med, Nov 19 (1998))

Response assessmentIn addition to conventional CT scans, metabolic imag-

ing using 2-[18F]Fluoro-2-deoxyglucose Positron Emission Tomography (18FFDG-PET or simply PET) has gained an in-creasing relevance in the response assessment in HL patients. A significant prognostic value of negative PET scans after completion of chemotherapy was described in a number of phase II trials. A number of ongoing trials currently evaluate the role of PET in prospectively randomized trials (see below).

Response-adapted chemotherapy treatment of HL is also currently being developed on the basis of interim PET scan results. Several phase II trials reported a negative pre-dicting value of more than 90% for interim PET. In addition, there was also a strong correlation between result of the early interim PET scan and progression free survival. However, the negative predictive value might vary dependent on the chemo-therapy regimen. A number of ongoing trials currently evalu-ate responseadapted treatment in HL patients based on the interim PET scan results.

Treatment of early favorable HLFor many years, large-field radiotherapy (RT) had been

the treatment of choice for early favorable HL. With this ap-proach, more than 70% of patients achieved complete remis-sion (CR); however, relapses were frequent and overall sur-vival (OS) was not satisfying. Studies by the EORTC demon-strated that three cycles of MOPP-ABV followed by involved-field RT (IFRT) led to a significantly better outcome than RT alone 3. Very similar, the GHSG HD7 clinical trial compared

extended-field RT (EFRT) only with a combination of two cycles of ABVD followed by the same RT. Tumor control was better in patients treated with the combined modality ap-proach (FFTF 88% versus 67% p

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Medicinski podmladakEditorijali


adapted treatment in this malignancy. Ongoing studies use PET after two courses of ABVD and treat with additional IFRT only in PET-positive patients. Studies including GHSG HD16, EORTC H10 as well as the UK PAPID trial will dem-onstrate whether consolidative RT is necessary in patients with metabolic CR after two cycles of ABVD. However, the question whether treatment can be stratified according to in-terim PET has not been answered yet. Treatment decisions based on interim PET should thus not be used outside clinical trials jet.

HL-related death of patients with early favorable dis-ease is unusual and overall survival is not a useful parameter for early evaluation in early-stage HL. Current trials should be judged by freedom from first recurrence rates and acute morbidity. On the basis of the available data, it can be con-cluded that patients with early favorable HL benefit from a short course of ABVD chemotherapy in combination with involved-field radiotherapy. Although there is some evidence that radiotherapy might not be necessary for patients in com-plete remission (CR) after two courses of ABVD chemothera-py, it is advisable to treat patients with early favorable HL with combined-modality since long-term results of patients treated with chemotherapy only are pending.

Early unfavorable HLIn the standard treatment defining EORTC/GELA

H8U study, 996 patients received either four or six cycles of MOPP/ABV followed by IFRT or four cycles of MOPP/ABV followed by either small field (IFRT) or large field (STNI) ra-diotherapy. There were similar rates for 5-year event-free sur-vival (EFS) and OS9. Thus the least toxic approach, i.e. four cycles of chemotherapy followed by IFRT, became standard of care for early unfavorable HL. Based mainly on trial results in advanced HL, ABVD was subsequently chosen as standard regimen for this group of patients.

In follow-up clinical trials such as the GHSG HD11 study10 and EORTC H9U11, the more intensive BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophospha-mide, vincristine, procarbazine, prednisone) in baseline dose was compared with ABVD. In this trial, chemotherapy was followed by either 30Gy or 20Gy IFRT. The final analysis re-vealed no significant outcome differences between the differ-ent regimens (figure 4).

Figure 4. Tumour control in early unfavorable HL (FFTF; HD11) (Eich HT et al, J Clin Oncol 28(27);20:4199-4206)

In contrast to early stage HL, however, IFRT with 30Gy was superior as compared to 20Gy radiation dose. Interim results of the EORTC H9U trial were similar. In this study, patients were randomized into three treatment arms consisting of four cycles of ABVD, six cycles of ABVD or four cycles of BEACOPPbaseline each followed by 30 Gy IFRT. An interim analysis at a median follow-up of four years showed no significant differences regarding EFS and OS be-tween treatment arms while increased toxicity was observed with BEACOPPbaseline. Consequently, ABVD followed by 30Gy IFRT remained standard of care in this group of pa-tients.

Significant outcome improvements in patients with early unfavorable HL were seen after the introduction of BEACOPPescalated in this setting: patients in the GHSG HD14 trial12 were randomized to either four cycles of ABVD fol-lowed by 30Gy IFRT or two cycles of BEACOPPescalated fol-lowed by two cycles of ABVD (2+2) and the same radio-therapy. The final analysis of this trial including 1623 patients showed that FFTF among patients who received the intensi-fied 2+2 chemotherapy was better compared with four cycles of ABVD (94.7% vs 89.3%). The GHSG has adapted 2+2 as new standard in their ongoing HD17 study for this patient population. Since there was no difference in survival between arms in HD14 so far, four cycles of ABVD chemotherapy fol-lowed by IFRT with 30Gy can still be regarded as a standard treatment for patients with early unfavorable HL.

It is unclear whether chemotherapy alone represents an option in this group of patients. Based on the results from the randomized Canadian/US HD.6 trial, patients achieving CR after 4-6 cycles of ABVD chemotherapy might not need ad-ditional RT. Final analyses of ongoing trials using interim PET-guided strategies will indicate whether this approach is feasible. Until then, interim PET-based treatment of early un-favorable disease must be restricted to clinical trials.

Advanced StagesBefore the introduction of multi-agent chemotherapy,

more than 95% of patients with advanced HL succumbed to their disease within few years13. The introduction of combina-tion chemotherapy such as MOPP or similar regimens in the 1960s led to long-term remission of up to 50%. An alternative regimen, ABVD, was developed a few years later by Bonadonna and colleagues in Europe resulting in significant-ly improved tumor control and OS14. The MOPP/ABVD hy-brid regimen and other alternating regimens were equally ef-fective as compared to ABVD, but more toxic. This included acute toxicity and the induction of secondary acute leukae-mias or MDS. Therefore ABVD became accepted as standard chemotherapy and was mainly used in combined modality strategies.

In order to further improve the outcome for this group of patients, new regimens were developed by integrating other drugs and increasing dose intensity. These new approaches included regimens such as Stanford-V, MEC, and BEACOPP (table 4).

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EditorijaliMedicinski podmladak


Table 4. Chemotherapy regimen in HL

Drug Dose (mg/m2) Route Schedule (days) Cycle Length (days)MOPP 21Mechlorethamine 6 IV 1, 8Oncovin (vincristine) 1.4 IV 1, 8Procarbazine 100 PO 114Prednisone 40 PO 114COPP 28

Cyclophosphamide 650 IV 1, 8Oncovin (vincristine) 1.4 IV 1, 8Procarbazine 100 PO 114Prednisone 40 PO 114ABVD 28Adriamycin (doxorubicin) 25 IV 1, 15Bleomycin 10 IV 1, 15Vinblastine 6 IV 1, 15Dacarbazine 375 IV 1, 15BEACOPP (baseline) 21

Bleomycin 10 IV 8Etoposide 100 IV 13Adriamycin (doxorubicin) 25 IV 1Cyclophosphamide 650 IV 1Oncovin (vincristine) 1.4a IV 8Procarbazine 100 PO 17Prednisone 40 PO 114BEACOPPescalated 22

Cyclophosphamide 1250 IV 1Adriamycin 35 IV 1Etoposide 200 IV 13Procarbazine 100 PO 17Prednisone 40 PO 114Oncovin (vincristine) 1.4a IV 8Bleomycin 10 IV 8G-CSF SC From d 8STANFORD V 12 wk

Mechlorethamine 6 IV Wk 1, 5, 9Adriamycin (doxorubicin) 25 IV Wk 1, 3, 5, 7, 9, 11Vinblastine 6 IV Wk 1, 3, 5, 7, 9, 11Vincristine 1.4a IV Wk 2, 4, 6, 8, 10, 12Bleomycin 5 IV Wk 2, 4, 6, 8, 10, 12Etoposide 60 IV Wk 3, 7, 11Prednisone 40 IV Wk 110 q.o.d.G-CSF PO Dose reduction or delay

A randomized comparison with MEC and ABVD showed inferiority of Stanford-V, but no significant difference between ABVD and MEC15. In a randomized phase III trial of the Eastern Cooperative Oncology Group, Stanford V was compared with ABVD: at a median follow-up of 5 years, PFS and OS of Stanford-V and ABVD were very similar while Stanford-V was more toxic16.

In 1992, the GHSG designed the BEACOPP regimen, both, in a baseline and an escalated version and compared these variants with COPP/ABVD in the HD9 trial. IFRT was used for bulky disease at diagnosis and for residual disease after eight cycles of chemotherapy17. At ten years follow-up, FFTF and overall survival were 82% and 86% with BEACOPP-escalated, 70% and 80% with BEACOPP-baseline and 64% and 75% in the COPP/ABVD (figure 5).

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Figure 5. Tumour control in advanced stage HL (FFTF; HD9) (Engert A et al, J Clin Oncol 27(27);20:4548-4554, 2009)

Importantly, the survival benefit became more evident with longer follow-up and was 11% at ten years when com-pared with COPP/ABVD 18. The higher efficacy of BEACOPPescalated was particularly evident in intermediate risk patients (IPS 2-3). However, toxicity of 8xBEACOPPescalated were a concern since this treatment was associated with more acute and long-term toxicity. The subsequent GHSG trials for advanced stage HL, HD12 and HD15, thus aimed at reducing treatment-associated toxicity by modifying the eight courses BEACOPP-escalated regimen and by revisiting the role of consolidative radiotherapy.

In HD1519, a total of 2.182 patients were randomized into the three study arms comparing eight cycles of BEACOPPescalated, six cycles of BEACOPPescalated and eight cy-cles of BEACOPP-14. FFTF at 5 years was 84.4% with eight cycles of BEACOPPescalated, 89.3% with six cycles of BEACOPPescalated, and 85.4% with eight cycles of BEACOPP-14. OS with six cycles of BEACOPPescalated was 95.3%, and also significantly better than the former standard treatment of eight cycles. Importantly, six cycles of BEACOPPescalated were also associated with a lower treatment-related mortality (0.8% vs 2.1%) and fewer cases of secondary acute myeloid leuke-mia (0.3 vs 2.7%) than eight cycles of BEACOPPescalated. Thus, the HD15 study showed that in patients with advanced stage HL, six cycles of BEACOPPescalated are better than eight cycles in terms of disease control and OS while being less toxic. Due to the better outcome and tolerability, 6 cycles of BEACOPPescalated followed by PET-guided RT to residual dis-ease became the new standard-of-care for advanced-stage HL within the GHSG and other groups. These date present the best lymphoma control and OS reported so far reported for advanced stage HL patients.

Another important question in HD15 was to possibly reduce the number of patients with additional radiotherapy. Patients with PET negative residual disease 2.5cm after the end of chemotherapy did not receive any additional RT and their outcome was not different from patients reaching a CR after chemotherapy. The negative predictive value (NPV) for PET was 94.1% at 12 months 19. With this PET-guided ap-proach, only 11% of all patients in this trial needed additional RT as compared to 70% in HD9.

Current concepts in advanced stage patients also in-vestigate early PET-adapted treatment. Strategies include in-creasing intensity of treatment for PET-2 positive patients af-ter ABVD or decreasing intensity in PET-2 negative patients after BEACOPPescalated. Until final results of these studies will be available, early PET-guided treatment-adaption is not ad-vised outside clinical trials.

Relapsed and refractor y H LHigh dose chemotherapy (HDCT) followed by autolo-

gous stem cell transplantation (ASCT) is the treatment of choice for HL patients who relapse after initial chemotherapy or are primary refractory to first-line treatment due to im-proved disease control compared to conventional chemother-apy20, 21. The benefit of HDCT and ASCT is significantly influ-enced by several prognostic factors such as time to relapse, anemia and stage at relapse. Various salvage chemotherapy regimens have been evaluated in single-arm trials. So far, there was only one randomized trial comparing different sec-ond-line induction regimens. This cooperative European trial, HDR2, demonstrated that two courses of DHAP followed by HDCT and ASCT are equally effective when compared to a more aggressive sequential high-dose-based induction treat-ment22. Thus, two courses of DHAP or similar regimens fol-lowed by HDCT and ASCT are considered standard of care for patients with relapsed HL.

Patients with primary refractory HL also benefit from HDCT and ASCT, but their outcome is poorer than for patients with relapsed HL. Thus, a tandem ASCT as suggested by a prospective multicenter phase II study of the GELA might be an appropriate approach for patients with primary refractory HL23.

New DrugsA number of promising new drugs are currently being

developed and evaluated in patients with relapsed or refrac-tory HL. The most advanced is Brentuximab Vedotin, an an-tibody-drug conjugate consisting of an anti-CD30 antibody conjugated to the potent anti-microtubule agent Monomethyl Auristatin-E (MMAE). In a phase I study that enrolled 45 pa-tients with CD30-positive lymphomas, the maximally toler-ated dose of SGN-35 was 1.8 mg/kg delivered as intravenous infusion every three weeks24. The subsequent phase II includ-ed relapsed HL patients after HDCT and ASCT. In this trial, 96 of 102 patients (94%) achieved tumor reduction; the overall response rate (ORR) was 75%, CR was achieved in 34% of patients25. The median PFS for all patients was 5.6 months and the median duration of response for those in CR 20.5 months. After a median observation time of over 1.5 years, 31 patients were alive and free of documented progressive disease (PD). The most common treatment-related adverse events were pe-ripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Based on these results, SGN-35 was approved for the treatment of relapsed HL patients after at least two prior lines of treatment. Further novel agents currently under-going clinical evaluation include monoclonal antibodies and small molecules.

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Reduced intensit y cond it ion ing a l logeneic stem cel l t ransplantat ion

Allogeneic stem cell transplantation (aSCT) represents a potentially curative treatment option for patients relapsing after ASCT but has to be considered experimental in HL since it is associated with relevant non-relapse mortality (NRM) and high relapse rates resulting in a long-term survival of only 30% to 40%. Sureda and colleagues recently reported results from a prospective phase II study including patients who underwent aSCT after induction chemotherapy with DHAP or other salvage protocols and reduced intensity condi-tioning with fludarabine and melphalan26. At one year, NRM rate was 15%. Cumulative relapse rates at one and four years were 37% and 59%, respectively. The estimated OS rate at four years was 43%. Patients not responding to the induction chemotherapy had a significantly worse clinical outcome. On the basis of these data, aSCT after reduced intensity condi-tioning cannot be recommended as standard approach in pa-tients failing HDCT and ASCT but might be used in selected patients. In particular, young chemosensitive patients may profit. Since optimization of aSCT in HL is necessary, treat-ment should be conducted within clinical trials only.

Nodular lymphocy te -predominant Hodgk in lymphoma

NLPHL accounts for about 5% of HL cases and differs from cHL in terms of histology, immunophenotype and clini-cal course. The detection of lymphocyte predominant (LP) cells is required for the diagnosis of NLPHL. A consistent expression of CD20 on the malignant cells is the hallmark of this disease; CD45 and the epithelial membrane antigen (EMA) are also frequently expressed. Particularly in patients with early-stage disease, the clinical course is often more in-dolent when compared with cHL27. Treatment with IFRT alone leads to excellent results in these patients and is widely considered standard of care for stage IA NLPH. In early unfa-vorable and advanced stages, the standard of care is very sim-ilar to cHL consisting of chemotherapy alone or combined modality approaches28. In relapsed NLPHL, standard treat-ment is undefined. However, impressive response rates of 90% to 100% and durable remissions in a relevant proportion of patients were observed after anti-CD20 antibody treat-ment29,30. Hence, it appears possible to spare HDCT and ASCT at least in patients with localized relapse.

Treatment of e lderly pat ients w ith Hodgk in lymphoma

According to cancer registries, HL patients aged 60 years or older account for about 20% of all cases in Western countries. Compared with younger patients, older HL patients have a significantly poorer clinical outcome. This is mostly due to the poorer tolerability of multi-agent chemotherapy 31. Since elderly patients are also often excluded from random-ized clinical trials, no standard of care for this age group has been defined yet. Most elderly patients in early favorable stag-es can be treated with the standard approach for younger pa-tients consisting of two cycles of ABVD followed by 20Gy IFRT. In early unfavorable stages, treatment with four cycles of ABVD followed by 30Gy IFRT is feasible in elderly pa-

tients although associated with an increased rate of toxic events 32. In advanced stages, most often six to eight cycles of ABVD are followed by localized RT of residual lymphoma. The BEACOPP protocol should not be applied in elderly pa-tients since increased toxicity and treatment-related mortality were observed in this age group. Treatment options in elderly patients with relapsed HL are very limited since the vast ma-jority is not eligible for HDCT and ASCT. Here, the anti-CD30 ADC Brentuximab Vedotin might offer new possibili-ties for this age group.

References1. DeVita VT Jr, Hubbard SM. Hodgkins disease. N Engl J

Med 1993;328(8): 560-5.2. Hasenclever D, Diehl V et al. A prognostic score for ad-

vanced Hodgkins disease. N Engl J Med 1998;339: 1506-1514.

3. Engert, A et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radio-therapy is superior to radiotherapy alone in early favorable Hodgkins lymphoma: final results of the GHSG HD7 tri-al. J Clin Oncol Aug 10 2007;25(23): 3495-502.

4. Raemaekers, J et al. The achievements of the EORTC Lymphoma Group. European Organisation for Research and Treatment of Cancer. Eur J Cancer 2002;38 Suppl 4, S107-113.

5. Engert, A et al. Reduced treatment intensity in patients with early-stage Hodgkins lymphoma. N Engl J Med 2010;363: 640-652.

6. Meyer, RM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkins lymphoma. N Engl J Med 2012;366: 399-408.

7. Hutchings, M et al. FDG-PET after two cycles of chemo-therapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 2006;107: 52-59.

8. Gallamini, A et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkins lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 2007;25: 3746-3752.

9. Ferme, C et al. Chemotherapy plus involved-field radiation in early-stage Hodgkins disease. N Engl J Med 2007;357: 1916-1927.

10. Eich, HT et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavor-able Hodgkins lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 2010;28: 4199-4206.

11. Thomas, J, Ferme, C & Noordijk, E. Results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial com-paring 3 chemotherapy schemes) in patients with favor-able or unfavorable early stage Hodgkins lymphoma. Haematologica 2007;92: 27.

12. von Tresckow, B, Pltschow, A, Fuchs, M et al. Dose-intensification in early favorable Hodgkin lymphoma: Final Analysis of the GHSG HD14 trial. J Clin Oncol Mar 20 2012;30(9):907-13.

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13. DeVita, VT Jr et al. Curability of advanced Hodgkins dis-ease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med May 1980;92(5):587-595.

14. Bonadonna, G, Valagussa, P & Santoro, A. Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkins disease. A report of 8-year results. Ann Intern Med 1986;104: 739-746.

15. Chisesi, T, et al. Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkins lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol Nov 10 2011;29(32):4227-33.

16. Gordon, LI, Hong, F, Fisher RI et al. A randomized phase III trial of ABVD vs Stanford V +/- radiation therapy in locally extensive and advanced stage Hodgkins lympho-ma: An intergroup study coordinated by the Eastern Cooperative Oncology Group. 52nd ASH Annual Meeting & Exposition, abstract 415 (2010)

17. Diehl, V et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkins disease. N Engl J Med 2003;348: 2386-2395.

18. Engert, A et al. Escalated-dose BEACOPP in the treat-ment of patients with advanced-stage Hodgkins lympho-ma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 2009;27: 4548-4554.

19. Engert, A et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkins lymphoma (HD15 trial): a randomized, open-label, phase 3 non-inferiority trial. Lancet 2012;379: 1791-1799.

20. Linch, DC et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkins disease: results of a BNLI randomised trial. Lancet 1993;341: 1051-1054.

21. Schmitz, N et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed che-mosensitive Hodgkins disease: a randomised trial. Lancet 2002;359: 2065-2071.

22. Josting, A et al. Dose intensity of chemotherapy in pa-tients with relapsed Hodgkins lymphoma. J Clin Oncol 2010;28: 5074-5080.

23. Morschhauser, F et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplanta-tion for first relapse/refractory Hodgkins lymphoma: re-sults of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol 2008;26: 5980-5987.

24. Younes, A et al. Brentuximab vedotin (SGN-35) for re-lapsed CD30-positive lymphomas. N Engl J Med 2010;363: 1812-1821.

25. Younes, A, Gopal, AK, Smith, SE et al. Results of a piv-otal phase II study of Brentuximab Vedotin (SGN-35) for patients with relapsed or rfractory Hodgkin lymphoma. J Clin Oncol 2012.

26. Sureda, A et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkins lymphoma. Results of the HDR-ALLO studya prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2012;97: 310-317.

27. Nogova, L, Rudiger, T & Engert, A. Biology, clinical course and management of nodular lymphocyte-predomi-nant hodgkin lymphoma. Hematology Am Soc Hematol Educ Program, 266-272 (2006)

28. Nogova, L et al. Lymphocyte-predominant and classical Hodgkins lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 2008;26: 434-439.

29. Schulz, H et al. Rituximab in relapsed lymphocyte-pre-dominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood 2008;111: 109-111.

30. Ekstrand, BC et al. Rituximab in lymphocyte-predomi-nant Hodgkin disease: results of a phase 2 trial. Blood 2003;101: 4285-4289.

31. Engert, A et al. Hodgkins lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkins Study Group. J Clin Oncol 2005;23: 5052-5060.

32. Boll, B et al. Feasibility and Efficacy of ABVD In Elderly Hodgkin Lymphoma Patients: Analysis of Two Randomized Prospective Multicenter Trials of the German Hodgkin Study Group (HD10 and HD11). ASH Annual Meeting Abstracts 116, 418- (2010)

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MODA NO STA BLOModano stablo je smeteno u zadnjoj lobanjskoj jami

i ine ga produena modina, pons i srednji mozak. Longitudinalne strukture su krov ili tektum, bazilarni region i tegmentom u sredini. Jedra svih lobanjskih ivaca, osim op-tikog i olfaktivnih, nalaze se u modanom stablu. Stablo je pokriveno malim mozgom sa kojim je povezano cerebelarnim kracima. etvrta modana komora nalazi se izmeu tegmen-tuma i krova. Senzitivna vlakna lobanjskih ivaca zavravaju se u jedrima, a motorna vlakna polaze iz motornih jedara u modanom stablu. Piramidni i senzitivni putevi prolaze kroz modano stablo. Povrede i oteenja modanog stabla manife-stuju se kao motorni, somatosenzitivni, cerebelarni i simpto-mi disfunkcije kranijumskih ivaca. Nivo lezije modanog stabla najee moe se otkriti na osnovu oteenog lobanj-skog ivca (Slika 1). Mala i pojedinana lezija moe izazvati teke i viestruke ispade (1)

Slika 1. Jedra lobanjskih ivaca. Dorzalni izgled modanog stable i lokalizacija jedara kranijumskih nerava.

Znaajan broj ukrtenih sindroma modanog stabla opisan je u neurolokoj literaturi, posebno tokom XIX i poet-kom XX veka. Veina ovih sindroma sastoje se iz ipsilateral-nog oteenja lobanjskog ivca i kontralateralne zahvaenosti

dugog puta, koja najee dovodi do hemipareze ili hemisen-zitivnih ispada. Vie od 25 alternih sindroma imenovani su prema autorima koji su ih prvi opisali (2). Izuzev Wallenbergovog sindroma, drugi klasini sindromi retko se sreu u klinikoj praksi. Veina je opisana na osnovu analize i prikaza pojedinanih sluajeva bolesnika, ponekada i na osnovu autopsijskih nalaza. U vreme tih prikaza nisu bile do-stupne metode neuroslikanja, niti funkcionalni testovi za pro-cenu i proveru pretpostavljene akutne lezije modanog stabla (2).

Jedra kranijumskih ivaca esto su oteena razliitim patolokim procesima koji zahvataju modano stablo. Oteenje jedra motornog nerva dovodi do paralize miia ko-je on inervie. Ova oduzetost je skoro uvek na strani otee-nja. Trohlearni ivac (n.IV) predstavlja izuzetak, jer se njego-va vlakna potpuno ukrtaju na zadnjoj strani. Neka vlakna okulomotornog ivca takoe se ukrtaju i izlaze sa vlaknima nerva suprotne strane. Oteenje motornog jedra kranijum-skog ivca dovodi do periferne paralize sa atrofijom zahvae-nog miia.

Kod lezija koje su lokalizovane lateralno, javie se znaci oteenja Edingerovog puta (kontralateralna analgezija i termanestezija). Ako se proces iri iz dorzolateralnog dela modanog stabla, oteenje silaznog simpatikog puta i po-vreda donjeg cerebelarnog pedunkula dovodi do pojave Hornerovog sindroma i istostranih cerebelarnih znakova. Dorzalna lezija modanog stabla najpre daje sliku povrede je-dara lobanjskih ivaca, zatim medijalnog lemniskusa (otee-nje dubokog senzibiliteta na suprotnoj strani) a kasnije i pira-midne ispade (hemiplegija ekstremiteta suprotne strane) (3). Ushodni somatosenzitivni putevi ukrtaju se u srednjem delu produene modine.

Piramidni putevi nalaze se u prednjim delovima me-zencefalona i produene modine. U najniim delovima pro-duene modine piramidni putevi se nalaze blizu jedan dru-gome pa i malo oteenje moe otetiti oba puta i dovesti do kvadripareze ili kvadriplegije. U bazilarnom delu ponsa, u kome su vlakna piramidnih puteva razdvojena u brojne snopo-ve, mala lezija moe biti kliniki neprimetna. U modanom stablu izuzetna je izolovana lezija piramidnih puteva jer se blizu njih nalaze kortikobulbusna vlakna koja odlaze u motor-na kranijumska jedra. Oteenje e u tom sluaju izazvati pa-ralizu i motornog kranijumskog ivca i ekstremiteta na su-protnoj strani. Lezije koje oteuju kortikospinalni i kortiko-bulbusni put esto zahvataju jedan ili vie kranijumskih nera-va (3).

Ishemija modanog stabla najei je uzrok akutnog oteenja. Najee pogaa modani most. Nevaskularni uz-roci ukljuuju demijelinacijsku bolest, degenerativne poreme-aje, povrede, neoplazme i dr. i najee daju multifokusna oteenja, pa imaju manju topografsku vrednost. Opisi ukr-

UKRTENI SINDROMI MODANOG STABLAProf. dr Neboja J. Jovi

Klinika za neurologiju i psihijatriju za decu i omladinu, Beograd, SrbijaMedicinski fakultet, Univerzitet u Beogradu, Srbija

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tenih sindroma modanog stabla bili su znaajni u definisa-nju vanih principa lokalizacije oteenja u modanom stablu (2).

A. SI N DROMI SR EDNJ EG MOZGA A.1. V ENTR A LNA OTEENJA SR EDNJ EG MOZGA

Jednostrano oteenje ventralnog dela srednjeg mozga moe ukljuiti modane pedunkule (kortikospinalni i korti-kobulbarni putevi). Oteenje anteromedijalnih struktura uzrokuje dizartriju ili disfagiju i slabost lica i ruke suprotne strane, bez senzitivnih ispada. Zahvaenost n.III i Westphal-Edingerovog jedra manifestuje se devijacijom oka na stranu lezije nanie i upolje, uz dilataciju zenice i ptozu. Lateralnije oteenje uzrokuje hemiparezu suprotne strane uz veu za-hvaenost noge, gubitak vibracijskog i poloajnog senzibilite-ta (medijalni lemniskus) na suprotnoj strani od oteenja i gubitak senzibiliteta za bol i temperaturu na trupu i ekstremi-tetima (ushodni spino-talamiki put). Horeoatetoza (crveno jedro), ataksija suprotne strane (gornji cerebelarni kraci) i in-ternukleusna oftalmoplegija (medijalni longitudinalni snop), Hornerov sindrom i sluna disfunkcija se ,takoe, mogu javiti (1).

A. 1.1. Weberov sindrom (H. Veber, 1863) Alterna okulomotorna hemiplegija

Herman David Weber (1823-1918) lekar Nemake bol-nice u Londonu 1863.g. prikazao je sluaj 52-godinjeg ove-ka sa desnostranom hemiparezom i paralizom levog okulo-motornog ivca koje su uzrokovane krvavljenjem i oteenjem

levog modanog kraka. Bolesnik je imao slabost desne strane lica, devijaciju jezika u desno, ptozu levog gornjeg onog kap-ka i midrijazu leve zenice. Levo oko je bilo okrenuto u stranu, uz ouvanu abdukciju i intorziju. Senzitivna diskriminacija dve odvojene take lica i tela sa desne strane bila je sniena (5, 6). Njegov bolesnik umro je dva meseca kasnije zbog bron-hopneumonije i pleuritisa. Autopsija je pokazala ateromato-zne promene unutranje karotidne arterije, bazilarne artrerije i leve srednje i zadnje arterije mozga. Raymond i Cestan su ovaj sindrom oznaili kao pedunkularni (4).

Weberov sindrom nastaje kao posledica oteenja je-dra i vlakana n.III (najee na izlazu iz tegmentuma) i mo-danog kraka i karakteriu ga:

1. kontralateralna hemiplegija/hemipareza (ukljuu-ujui i donji deo lica), zbog zahvaenosti kortiko-spinalnog i kortikobulbarnog puta.

2. ipsilateralna spoljna okulomotorna pareza, uklju-ujui i parasimpatiki deo nerva (dilatacija zeni-ce). Potpuna zahvaenost n.III dovodi do ipsilate-ralne ptoze, dilatacije zenice, gubitka pupilarnih refleksa i reakcije na akomodaciju i lateralne devi-jacije oka (7).

Klinike manifestacije infarkta srednjeg mozga naje-e jasno i direktno odgovaraju lokalizaciji lezije, ali se one ne poklapaju uvek sa klasinim, izvornim, opisom (6, 8). Ovo je ee kod bolesnika sa istorijom dugotrajne arterijske hiper-tenzije i eerne bolesti. Veberov sindrom najee je posledi-ca okluzije (uglavnom emobolijskog tipa), paramedijalnih perforantnih, pedunkularnih i interpedunkularnih grana zad-nje modane arterije (Slika 2).

Slika 2 Weberov sindrom. (A) T1-weighted MR postkontrastno pojaana lezija, lokalizovana levo u srednjem mozgu i moda-nom pedunkulu (B) T2-weightedoteenje koje zahvata srednji mozak, modani krak i optiki put s leve strane

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Prikazan je sluaj bolesnice sa Weberovim sindromom i normalnom zenicom. Ishemijska lezija donjeg srednjeg mo-zga, viena na MR pregledu mozga, ukljuila je motorno je-dro n.III. ali ne i Westphal-Edingerovo jedro, ime se obja-njava takav nalaz (7). Weberov sindrom vaskularne etiologi-je moe imati povoljan ishod uz reverzibilni tok ukrtene pa-ralize (6). Netipini sluajevi ukrtene hemiplegije sa parali-zom n.III i n.VII koje su izazvane infarktom posteriorne cir-kulacije, ukljuujui ventro-medijalni kruralni region sred-njeg mozga, veoma su retki (8, 9). Opisani su brojni sluajevi nevaskularne etiologije Veberovog sindroma, ukljuujui aneurizmu, tumor, demijelinaciju, primarni limfom CNS i ne-urocisticerkozu jedne strane ventralnog srednjeg mozga (10).

A.1.2. Benediktov sindrom (M. Benedikt, 1889)Originalni sluaj koji je opisao Benedikt imao je tuber-

kulozu mozga. Lezija ventralnog tegmentuma srednjeg mo-zga sa zahvaenou crvenog jedra, modanih pedunkula i okulomotornih snopova izaziva Benediktov sindrom koji i-ne:

1. istostrana okulomotorne paraliza, najee uz dila-teranu zenicu

2. kontralateralni nevoljni pokreti- hiperkinezije (in-tencioni tremor, hemihorea, hemiatetoza), koji na-staju zbog lezije crvenog jedra.

Benediktov sindrom najee je uzrokovan stenozom proksimalne zadnje modane arterije (12). Prikazan je i sluaj sa naglim razvojem diplopija, desnostrane ptoze, retrakcije levog kapka, lake levostrane hemipareze i nevoljnih pokreta. Zakljuena je istovremena pojava dva mezencefalika sindro-ma (Benediktov i plusminus lid sindrom-jednostrana re-trakcija kapka sa kontralateralnom ptozom) izazvani odvoje-nim infarktima srednjeg mozga posle okluzije vie malih gra-na distalne bazilarne aretrije i proksimalnih, paramedijalnih i pedunkularnih perforantnih arterija. Angiografija je pokazala teku stenozu proksimalnog segmenta desne zadnje modane aretrije (13).

A.1.3. Claudeov sindrom (H. Klod, 1912)Claude je 1912. opisao molera kod koga se razvila de-

snostrana paraliza okulomotornog ivca i kontralateralana ataksija hoda. Patoloki pregled njegovog bolesnika otkrio je infarkt u desnom paramedijalnom delu srednjeg mozga, koji je ukljuio gornje cerebelarne pedunkule i medijalnu polovi-nu crvenog jedra (14). Klodov sindrom je ukrteni sindrom srednjeg mozga koji nastaje zbog simultane zahvaenosti ce-rebelarnih dentato-talamikih vlakana i snopova n.III i karak-terie se ipsilateralnom oduzetou okulomotornog ivca i kontralateralnom hemiataksijom (15).

Cerebrovaskulni poremeaji i tumori su najea etio-logija. Okluzija perforantnih arterija koje potiu iz zadnje mo-dane arterije pretpostavljena je najea vaskularna osnova ovog sindroma (9). Neurocisticerkusna infekcija retko izaziva Klodov sindrom (16). Iako neki raniji prikazi podravaju ori-ginalnu zahvaenost crvenog jedra (14), veina prikaza suge-rie kljunu leziju gornjeg cerebelarnog kraka, ispod i unutra od crvenog jedra (16, 17). (Slika 3). Samo retki sluajevi po-kazuju dodatnu zahvaenost crvenog jedra.

A.2 . DOR ZA LNA OTEENJA SR EDNJ EG MOZGA

Ova oteenja uglavnom izazivaju neuro-oftalmoloke poremeaje i viaju kod hidrocefalusa i tumora pinealnog re-giona.

Slika 3 a. Claudeov sindrom. MR mozga (FLAIR). Hiperin-tenzna lezija u levom ventro-medijalnom srednjem mozgu (3a).

Slika 3 b. Claudeov sindrom. MR mozga (FLAIR). Oteenje lokalizovano u gornjem cerebelarnom kraku, ispod i medijal-no od crvenog jedra (3b)

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A.2 .1. Par inaud- ov s indrom ( Par ino, 1883, 1886)

A.2.2 Koerber Salus Elschnigov syndrome (1903, 1910)Ova dva sindroma se ne mogu smatrati klasinim ukr-

tenim sindromima modanog stabla, s obzirom na odsustvo oteenja dugih puteva u modanom stablu. S obzirom na to da su praeni oftalmolokim i neurolokim znacima koji uka-zuju na tipine lezije modanog stabla, oni su esto ukljueni u listu alternih sindroma ove strukture.

Parinaudov sindrom (18) se odlikuje paralizom konju-govanog vertikalnog pogleda i pokreta oiju i slabou kon-vergencije uz druge neuro-oftalmoloke znake (iroke i ne-pravilne zenice, retrakcija kapka, nistagmus pri konvergenci-ji, slabost akomodacije). Koerber Salus Elschnigov sindrom se negde izdvaja kao poseban entitet i pored znaajnog prekla-panja sa Parinaudovim sindromom koji se karakterie retrak-tornim nistagmusom, paralizom vertikalnog pogleda, pore-meajima pupile i znacima bolesti srednjeg mozga (15). U ni-zu prikaza bolesnika sa Parinaudovim sindromom, zapaena je poteenost okulomotornih jedara i pretpostavljeno je ote-enje rostralnih intersticijskih jedara medijalnog longitudi-nalnog snopa ili eferentnih puteva koji posreduju u pogledu navie (1,19,20).

B. MODA NI MOST

PONTINI ALTERNI SINDROMI

B.1. Millard-Gublerov sindrom (A. Milar, A. Gubler, 1856)

Auguste Millard (1830-1915) prvi je saoptio Anatomskom udruenju u Parizu zapaanje po kome je peri-ferna paraliza lica na strani oteenja udrena sa kontralate-ralnom hemiplegijom znak pontine hemoragije. Opisao je bo-lesnika sa takvim nalazom i naveo je jo jedan sluaj prodavca voa i povra ija autopsija je otkrila 5 mm veliku zonu raz-mekanja sa sredinjim krvavljenjem u srednjem ponsu. Adolphe Gubler (1821-1897) opisao je dodatnih 6 sluajeva. Njegov prvi pacijent bila je ena sa plunom tuberkulozom, desnostranom hemiparezom i slabou leve polovine lica. Gubler je zakljuio da su opisane ukrtene paralize vezane za oteenje ponsa. Nepromenjenu inteligenciju smatrao je po-kazateljem ouvanih funkcija modanih hemisfera. Originalni bolesnici Millarda i Gublera nisu imali paralizu VI ivca a ventro-kaudalna lezija ponsa verovatno je zahvatila kortiko-spinalni put i snop VII (21, 22).

Ovaj sindrom zahvata lice na strani lezije i ekstremite-te na suprotnoj strani Njaee unilateralno oteenje bazal-nog dela ventro-kaudalnog ponsa ukljuuje kortikospinalni put i vlakna abducensa i facijalnog lobanjskog ivca. Kao po-sledica ove lezije nastaju:

1. periferna paraliza/pareza lica (VII) na strani otee-nja

2. kontralateralna hemiplegija (uz potedu lica) zbog zahvaenosti piramidnog puta pre njegovog ukrtanja,

3. istostrana pareza pravog spoljanjeg miia oka, (VI) sa dvoslikama koje se naglaavaju pri pogledu u stranu lezije

Strukturna oteenja tegmentuma donjeg dela moda-nog mosta izazvana tumorima i krvavljenjem a retko i infark-tom koji nastaje zbog okluzije bazilarne arterije mogu dati sliku ovog sindroma. Krvavljenja iz kavernoznog hemangio-na jedne strane ponsa opisano je kao mogua etiologija (23) (Slika 4).

Bolesnici mogu imati i druge neuroloke ispade koji su posledica oteenja struktura blizu jedra facijalnog ivca, kao to su hemiparestezija i cerebelarna ataksija na suprotnoj stra-ni od lezije (24). Prikazan je sluaj 3-godinje devojica sa desnostranom oduzetou n.VI i n.VII i levostranom hemipa-rezom koje su uzrokovane tuberkuloznim granulomom mo-danog stabla (desna polovina mosta, uz irenje lezije prema desnom srednjem cerebelarnom kraku i srednjem mozgu). Uz antituberkuloznu terapiju dolo je do znaajnog poboljanja neurolokih ispada (25).

B.2. Foville-ov sindrom (A.L. Fovil, 1858)Achille Louis Foville (1799-1878) opisao je 43-godi-

njeg bolesnika sa desnostranom slabou ekstremiteta, pot-punom levostranom paralizom lica i nemogunou da gleda u levu stranu (paraliza konjugovanih pokreta). Pretpostavio je da je za ove ispade odgovorna jednostrana lezija modanog mosta i da je paraliza pogleda posledica oteenja jedra abdu-censa na strani oteenja (26).

Slika 4. Millard Gublerov sindrom. MR mozga pokazuje hemoragiju koja potie iz kavernoznog hemangioma u ponsu sa leve strane

Ovaj sindrom je posledica lezije dorzalnog pontinog tegmentuma u donjoj treini ponsa. Sastoji se od:

1. kontralateralne hemiplegije (uz potedu lica) zbog zahvaenosti piramidnog puta,

2. ipsilateralne periferne facijalne paralize zbog za-hvaenosti jedra i snopova n. VII,

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3. nesposobnosti konjugovanog pomeranja oiju na is-tu stranu (devijacija pogleda ka zdravoj strani) zbog zahvaenosti paramedijalne retikularne pon-tine formacije i/ili jedra abducensa (15).

Opisano je nekoliko varijanti ovog sindroma:Pontini Fovilov sindrom pored kontralateralne hemi-

plegije odlikuje se paralizom abducensa.Gornji Fovilov sindrom sastoji se od ukrtene hemi-

plegije, istostrane paralize okulomotornog ivca i kontralate-ralne paralize lica.

Donji Fovilov sindrom karakterie se hemiplegijom suprotne strane i istostranom paralizom okulomotornog i fa-cijalnog ivca (3).

Nagla, prolazna pojava dvoslika i hemipareze moe ukazati na poetni razvoj medijalnog donjeg pontinog sindro-ma (27). Fluktiuirajui Fovilov sindrom prikazan je kod bole-snika sa kavernoznim angiomom dorzalnog ponsa i hroni-nim bubrenim poputanjem zbog policistinih bubrega. Lokalizovani mali hematom u pontinom angiomu, nastao to-kom hemodijalize, uzrokovao je paralizu konjugovanog po-kreta oiju u stranu lezije i kontralateralnu hemiparezu (28).

Milar-Gublerov sindrom treba razlikovati od Fovilovog syndrome, kod koga postoji i slabost pogleda u stranu. To je zato to kod Fovilovog sindroma zahvaeno jedro n.VI, koje sadri interneurone koji povezuju unutranji longitudinalni snop sa podjedrom za unutranji pravi mii okulomotornog kompleksa suprotne strane. To dovodi do potpune oduzetosti pokreta oka u stranu zbog slabost ipsilateralnog pravog spolj-nog i kontralateralnog unutranjeg pravog miia (27).

B. 3.1. Reymondov s indrom ( F-Remon 1895)

B.3.2 Reymond-Cstanov sindrom (F. Remon, R. Sestan, 1901-1903)

Fulgence Raymond (1844-1910), naslednik Charcota na mestu profesora u Klinici za nervne bolesti Salptrire u

Parizu, opisao je oteenje levog abducensa i kontralateralnu hemiparezu kod jedne ene sa sifilisom. Pretpostavio je da lezija donjeg ponsa moe istovremeno da oteti i piramidni put i n.abducens, ali poteuje facijalni ivac koji je lateralni-je poloen. S druge strane, njegova pacijentkinja je jasno ima-la brojne druge lezije i desnostranu facijalnu paralizu, afaziju, prozopagnoziju i diplopije. Raymond je opisao i strukturu modanih pedunkula, ukljuujui kortikobulbarna vlakna od motorne kore kroz koleno unutranje kapsule do ukrtanja u ponsu i njihove inervacije jedra facijalnog ivca (29).

U periodu od 1901-1903. Raymond i Cestan (1872-1934) (30) opisali su tri sluaja. Svi bolesnici imali su internu-kleusnu oftalmoplegiju, bez devijacije oiju u primarnom po-loaju. Konvergencija bulbusa i zenice bili su normalni. Postojali su senzorimotorni poremeaji, kontralateralno od slabosti adukcije bulbusa. Slabost ekstremiteta bila je laka, ali voljni motorni pokreti bili su veoma poremeeni, uz krupan statiki tremor, atetozne pokrete prstiju, ataksiju, dismetriju i asinergiju. Hipoestezija i astereognozija su ,takoe, zapaene.

U svim sluajevima ukrtena paraliza bila je uzroko-vana pojedinanim tuberkulumom u rostralnom tegmentumu. Autori su oznaili ovaj sindrom kao gornji pontini (syndrome protuberatiel superieur). Naglasili su da se paraliza konjugo-vanih pokreta oiju kod njihovih bolesnika odvija bez zahva-enosti jedra n.VI i da je tuberkulom mogao indirektno da ga oteti. Pretpostavili su da je slabost horizontalnih pokreta oi-ju (internukleusna oftalmoloplegija) uzrokovana destrukci-jom longitudinalnog medijalnog snopa.

Raymondov sindrom pripada grupi anteromedijal-nih/anterolateralnih sindroma i sastoji se iz ipsilateralnog oteenja abducensa (oduzetost spoljnog pravog miia na strani lezije) i hemipareze suprotne strane. Kortikospinalni i kortikobulbarni put prolaze kroz ventromedijalnu zonu kau-dalnog ponsa. Veina bolesnika ima ishemijsko oteenje pa-ramedijalnog i lateralnog dela baze kaudalnog ponsa i MR mozga pokazuje infarkt ove strukture (Slika 5).

Slika 5. Raymondov sindrom. MR mozga (T2 sekvencija) pokazuje zonu nenormalno visokog intenziteta u paramedijalnom i spoljanjem delu baze kaudalnog ponsa, sa leve strane (strelice)

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Udruenost Raymondovog sindroma i supranukleusne paralize facijalnog ivca zbog infarkta u nivou baze moda-nog mosta retko se opisuje (31). Mali hematom medijalnog ponto-medularnog spoja moe dati sliku ovog ukrtenog sin-droma (32).

Predloen je koncept po kome postoje dva klinika tipa Raymondovog sindroma: 1) klasini tip, koji je izazvan ote-enjem srednjeg ponsa , koje ukljuuje ipsilateralni snop ab-ducensa i neukrtena kortikofacijalna i kortikospinalna vlak-na (ipsilateralno oteenje n.VI, kontralateralna centralna fa-cijalna pareza i kontralateralna hemipareza), 2) obian, jedno-stavan tip, koji moe biti uzrokovan zahvatanjem ipsilateral-nog snopa n.VI i neukrtenih kortikospinalnih vlakana, uz potedu kortikofacijalnih vlakana (bez facijalne slabosti) i ee je opisivan u kasnijim klinikim zapaanjima (31).

Reymond-Cstanov sindrom via se kod rostralnih lezija dorzalnog ponsa (povreda medijalnog lemniskusa i lon-gitudinalnog medijalnog snopa). Ukljuuje:

1. Ataksiju (sa grubim, rubralnim tremorom)(15),2. kontralateralni poremeaj senzibiliteta lica, ekstre-

miteta (hemianestezija ili hemihipestezija), zbog zahvaenosti medijalnog lemniskusa spinotalami-kog trakta.

3. kontralateralna hemipareza (1) i mogua paraliza konjugovanog pokreta oiju ka strani lezije zbog zahvaenosti paramedijalne retikularne pontine formacije (15).

B. 4 . Mar ie -Foi x s indromOpisuje se kod dorzo-lateralnih oteenja ponsa (po-

sebno brachium pontis). Sastoji se iz:1. ipsilateralne cerebelarne ataksije, 2. kontralateralne

hemipareze, 3. promenljive kontralateralne hemihipestezije za bol (hemihipalgezija) i temperaturu (zahvaenost Edingerovog puta) (15).

B. 5 . Gasper in ijev s indrom ( U. Gasper in i , 1912)Italijanski internista Ubaldo Gasperini je 1912.g. opi-

sao bolesnicu sa lezijom lobanjskih nerava V-VIII s jedne strane, perifernom facijalnom paralizom, perifernom oduze-tou abducensa i paralizom pogleda u obolelu stranu, udru-enim sa hipakuzijom suprotne strane i hemisenzitivnim is-padima -kontralateralnom hemihipestezijom za bol (hemihi-palgezija) i temparaturu tela nie od vrata (33, 34). U poetku se moe javiti i laka motorna slabost (33). Nagli nastanak kli-nikih simptoma ukazuje je vaskularno poreklo ispada. Gasperini je pretpostavio uzrono krvavljenje u modanom stablu, lokalizovano u lateralnom, kaudalnom tegmentumu modanog mosta. Njegov prikaz je sugerisao mogunost da se u sliku ukljue i periferna oduzetost trigeminusa i gluvoa na strani lezije. Nije raena autopsija koja bi podrala Gasperinijevo kliniko zapaanje.

Gasperinijev sindrom nastaje kao posledica male ishe-mike, infarktne ili hemoragine lezije mediolateralnog pon-tinog tegmentuma (34).Anatomska osnova za ovaj sindrom ukljuuje jednostrano oteenje jedra facijalnog ivca (peri-ferna facijalna paraliza), n. abducensa (paraliza pogleda pre-ma strani lezije) ili intrapontinih segmenata ovih ivaca), aku-stikih vlakana (hipakuzija), spinalnog trigeminusnog puta

(hipestezija lica) i spinotalamusnog puta (kontralateralna he-mihipestezija za bol i temperaturu). Paraliza pogleda u stranu lezije javlja se retko i smatra se posledicom zahvaenosti pa-rapontine retikularne formacije. Ukoliko bi bila izraena dija-gnoza Fovilovog sindroma bi bila razmatrana (27,34).

Slika 6. Gasperinijev sindrom. MR mozga (FLAIR) pokazuje zonu povienog intenzioteta signala u levostranom lateral-nom, kaudalnom tegmentumu modanog mosta

Najvei broj sluajeva opisan je u japanskoj literaturi. Neuroslikanje pokazuje da je Gasperinijev sindrom ishemi-ke etiologije uglavnom vezan za oteenje duge cirkuferentne grane prednje donje cerebelarne arterije (34). Prikazan je i sluaj bolesnika sa klasinim sindromom koji je uzrokovan pontinom demijelinacijom u sklopu multiple skleroze (35). Neki autori sumnjaju u autentinost inicijalnog opisa ovog sindroma i vezanost za Gasperinijevo ime (2). (Slika 6)

Iako prikazi sluajeva sa Gasperinijevim sindromom nisu esti, vidljiva je znaajna heterogenost klinike slike. Gasperinijev originalni prikaz opisao je kontralateralni gubi-tak senzibiliteta zbog oteenja spinotalamikog puta. U ne-kim sluajevima ukljuen je trigeminotalamusni put dovodei do poremeaja senzibiliteta polovine lica suprotne strane. Gubitak sluha je est, ali je vertigo izuzetano redak. Prikazana je udruenost jednostrane trigemino-autonomne glavobolje (kratkotrajni napadi fronto-periorbitalnog bola umerene jai-ne, praenog suzenjem i lakom kongestijom venjaa tokom jaih nastupa na strani lezije) kod bolesnika sa Gasperinijevim sindromom koji je uzrokovan okluzijom desne prednje donje cerebelarne arterije. MR mozga je pokazala infarkt desnog cerebelarnog kraka, koji se prostire do pontinog tegmentuma i ukljuuje spinalno trigeminusno jedro i snop iste strane (36).

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PRODUENA MODI NA

C. 1. Wallenbergov (lateralni medularni) sindrom /A. Valenberg, 1895)

Najraniji poznati prikaz lateralnog medularnog infark-ta dao je 1810. godine Gaspard Vieusseux iz Geneve, u Medicinskom i Hirurkom Drutvu u Londonu. Vertigo, jed-nostrana facijalna pareza, gubitak oseaja za bol i temperatu-ru u kontralateralnim ekstremitetima, disfazija i promuklost, zahvaenost jezika, tucanje (dobro je reagovalo na uzimanje jutranje cigarete) i unilateralna ptoza.

Adolf Wallenberg, nemaki lekar, posle studija u Hajdelbergu i Lajpcigu, najvei deo strune prakse obavljao je u Danzigu. Pored rukopisa koji se odnose na patoantomske i patofizioloke aspekte CNS, njegov najvei doprinos odnosi se na lateralni medularni sindrom (LMS). Wallenbergov pri-kaz sluaja 1895.g. upotpunio je kliniku sliku tanom lokali-zacijom oteenja, odgovornog za zapaene ispade, koje je kasnije potvreno u obdukcionom nalazu. On je objavio 4 ra-da koji opisuju sluajeve sa LMS. U njima je sugerisao otee-nje lateralne modine zbog poremeaja snabdevanja krvlju iz zadnje donje cerebelarne arterije posle stenoze ili potpune okluzije (37, 38) (Slika 7).

Ovaj sindrom je najee posledica okluzije vertebral-ne ili zadnje donje cerebelarne arterije, disekcije vertebralne arterije, ali se javlja i kod kokainomana, metastaza u produe-noj modini, radionekroze i hematoma posle rupture vasku-larne malformacije (15). Angiografija nainjena kod 123 bole-snika sa laterlanim medularnim infarktom pokazala je bolest vertebralne arterije kod 67% i zadnje donje cerebelarne arte-rije kod 10%. Najea vaskularna patologija ukljuila je in-farkt (ee veih nego manjih krvnih sudova), disekciju arte-rija i srani embolizam. Izolovana patologija zadnje donje cerebelarne arterije ee je bila vezana za srani embolizam nego za arterijsku disekciju (39). Prikazan je sluaj LMS na-stalog posle traumatogene disekcije vertebralne arterije i ra-zvoja infarkta zadnje donje cerebelarne arterije, posle lakog saobraajnog udesa u kome je povreeni uestvovao kao mo-torciklista. Autori sugeriu mogunost infarkta zadnje cirku-lacije i kod mladih odraslih osoba, ak i posle trivijalne po-vrede glave i vrata (40).

Slika 7. Produena modina u nivou donjeg olivarnog jedra

Pretpostavlja se da ekstraduralno poreklo zadnje donje cerebelarne arterije moe predisponovati za ne-traumatski lateralni medularni sindrom posle naglih ili ponavljanih pokreta glave i vrata. Uz normalan angiografski nalaz , sma-tra se da neuroloka slika nastaje zbog prekida hemodinamsk-og protoka i prolaznog arterijskog spazma uzrokovanog mehanikom silom (pritisak ili rastezanje) na krvni sud tokom pokreta glave i vrata.Veoma retko, multipla skleroza moe izazvati LMS. Izolovana zahvaenost donjeg modanog stab-la retka je inicijalna prezentacija multiple skleroze. Prva eg-zacerbacija bolesti, pod odreenim uslovima moe izazvati dijagnostiku konfuziju i liiti na log (41) (Slika 8).

Slika 8. a/b. Wallenbergov sindrom izazvan multiplom sklerozom. MR (aksijalni i sagitalni) pregled modanog stabla i vratne kimene modine pokazuje lateralni medularni demijelinacijski plak

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Klinika slika odraava oteenje lateralne medule i donjeg cerebeluma :

Na strani lezije (ipsilateralno):poremeaji gutanja sa bitonalnim glasom zbog paralize IX, X i XI-M ivca i oteenja jedra ambiguusa (ipsilateralna para-liza nepca, drela i jedne glasnice), Claude-Bernard-Hornerov sindrom, vestibularni poremeaji sa rotatornim nistagmusom, vrtoglavicom, muninom i povraanjem (za-hvatanje vestibularnih jedara); hipalgezija i termoanestezija polovine lica, najee oftalmine zone trigeminusne inerva-

cije (spinalno trigeminusno jedro i put); cerebelarni znaci i simptomi na istostranoj nozi (zahvaenost donjeg cerebelar-nog pedunkula).

B. na suprotnoj strani od uzronog oteenja:kontralateralna hipalgezija i termanestezija trupa i ekstremi-teta (spinotalamiki put), najee poteujui lice (42)

Piramidni sistem, pokretljivost jezika i vibracijski i po-loajni senzibilitet tipino su poteeni zato to je njihova anatomska osnova vezana za medijalni deo produene modi-ne.

Slika 9. a/b. Wallenbergov sindrom. MR mozga (FLAIR) hiperintenzitet u desnoj lateralnoj produenoj modini i desnom cerebelumu. 6b-Diffusion-weighted MR pokazuje istu leziju koja odgovara skorom infarktu

Poremeaji pokreta oiju koji su opisani uz lateralni medularni sindrom su: lateropulzija prema strani lezija, skew devijacija, nistagmusni trzaji onih kapaka, konjugovana de-vijacija oka na stranu lezije pri zatvorenim kapcima. Postoje nepotpuni oblici sindroma, ali i oni koji ga prevazilaze i ukljuuju ipsilateralne okulomotorne oduzetosti (42). Kliniko-radioloka analiza 130 bolesnika sa akutnim lateral-nim medularnim infarkom pokazala je da rostralna lezija es-e dovodi do disfagije, facijalne pareze i dizartrije a ree do teke ataksije hoda i glavobolje u poreenju sa kaudalnim oteenjem (39) (Slika 9).

Kompletni oblik LMS ukljuuje vertigo, muninu, po-vraanje, disfagiju, tucanje, nistagmus, ataksiju, ipsilateralni gubitak senzibiliteta lica i Hornerov sindrom i kontralateralnu spinotalamiku hemianesteziju tela. Nepotpuni oblici javljaju se esto i predstavljaju razliite kombinacije ovih klinikih simptoma i znakova. Sluajevi LMS u kojima ukrtenost neu-rolokih ispada nedostaje ili je delom izraena, prikazani su. Hipalgezija koja ukljuuje lice, trup i ekstremitete na suprot-noj strani u odnosu na leziju, bez zahvaenosti istre strane li-ca, povremeno se opisuje (43). Prikazani su i bolesnici sa ipsi-lateralnom aksijalnom lateropulzijom kao poetnim simpto-mom okluzije vertebralne arterije. Oteenje vestibularnih

jedara, gornjeg i donjeg cerebelarnog kraka i donjeg dela ma-log mozga i spino-cerebelarnog puta smatra se moguom ana-tomskom osnovom za pojavu aksijalne lateropulzije (44).

Kliniki razvoj Wallenbergovog sindroma najee ima povoljnu prognozu. Najvei problem predstavljaju bolovi polovine tela sa hipoestezijom, spino-talamikog porekla. Centralni hronini bol nastaje kod 15-25% bolesnika sa LMS posle lateralnog medularnog infarkta, u periodu tokom 6 me-seci posle insulta. Stalan je, jak, arei i sa estom alodinijom, pojaava se sa hladnoom i mehanikim nadraajima. Najee zahvata ipsilateralni peri-orbitalni region lica (retko sa neurotrofinom ulceracijom) i kontralateralne ekstremitete (45) u sklopu selektivne lezije spino- i trigemino-talamikog sistema. Ipsilateralni facijalni bol moe biti stalan ili intermi-tentan a povremeno ima svojstva kratkih napada karakteri-stinih za trigeminusnu neuralgiju. Prikazani su i bolesnici sa bolnim, paroksizmalnim nastupima u inervacijskim zonama trigeminusa, koji su nastali nekoliko nedelja posle medular-nog infarkta (46) .

Primena MR mozga i neinvazivnih neuroslikanja krv-nih sudova delom su modifikovali prethodni koncept klini-kog spektra i uzroka razliitih tipova infarkta modanog sta-bla (Slika 10). Wallenbergov sindrom esto pokazuje obrasce

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senzitivnih ispada, razliitog od klasinog ukrtenog tipa. Infarkti bonog dela produene modine udrueni su sa rizi-kom od respiratornih i kardiovaskularnih komplikacija u akutnoj fazi, to zahteva brino nadgledanje bolesnika (47). Razlike u topografskom obrascu infarkta u donjem delu mo-danog stable najverovatnije odraavaju razlike u etiopatoge-netskim mehanizmima. Skoranji prikazi opisuju neoekiva-ni nagli kardiorespiratorni zastoj kod bolesnika sa lateralnim medularnim infarktom tokom perioda oporavka posle loga sa minimalnom motornom onesposobljenou. Pretpostavljeni su: srana aritmija, ishemina zona koja zahvata srane i re-spiratorne centre u produenoj modini. Ove medularne lezije izazivaju autonomnu nestabilnost koja dovodi do smrti. (48)

Slika 10. Wallenbergov sindrom. MR mozga (aksijalni FLA-IR) pokazuje lateralni medularni infarkt

C.2 . MEDIJA LNI MEDU LA R NI SI N DROM

C.2.1 Dejerineov (Deerin, 1926) SindromU sklopu medijalnog medularnog sindroma (MMS),

najei je klasini Dejerineov (Deerin) sindrom. Ateroskleroza i distalna okluzija vertebralne arterije, atero-matozna bolest penetrantnih arterija ili okluzija gornjeg dela prednje spinalne arterije najei su uzroci infarkta medijalne modine (1, 9). Disekcija vertebralne arterije, iako ea kod Wallenbergovog sindroma, utvrena je kao vaan etioloki inilac i za medijalni sindrom (49). eerna bolest je esta kod bolesnika sa MMS.

Neuroloki nalaz sastoji se iz kontralateralne hemipa-reze, lemniskusnog gubitka senzibiliteta i paralize jezika na strani lezije.Oteenje piramidnog puta u medijalnoj modini dovodi do pareze ruke i noge na suprostnoj strain od lezije i u polovini sluajeva i do pareze suprotne strane lica. Hipoglosni ivac je esto oteen, to do void do istostrane slabosti jezi-ka. Vibracijski i senzibilitet za poloaj i sterognozija na kon-tralateralnim ekstremitetima mogu biti poremeeni uz pote-du osetljivosti za bol i temperature. Poremeaj svesti, opisan

kod nekih od njih bio je blag i prolazan i uglavnom je bio po tipu pospanosti i zbunjebnosti.

C. 3. Hemimedularn i Babinsk i -Nageot teov s in-drom (. Babinsk i , . Naot , 1902)

Otkada su Babinski i Nageotte opisali autopsijski na-laz ishemijske lezije unilateralne produene modine, opisi hemimedularnog infarkta retki su ili su osporavani. Oni su opisali hemiasinergiju, hemiataksiju sa lateropulzijom i mio-zu na strani lezije, a hemianesteziju i hemiplegiju na suprotnoj strani (50). U ranim klinikim prikazima hemimedularnog sindroma uglavnom se isticao fatalni ishod, naroito ako je tok komplikovan respiracijskim poremeajima (51). Babinski-Nageotteov sindrom se moe posmatrati kao retka kombinaci-ja medijalnog i lateralnog medularnog sindroma. Nuhalni bol i Wallenbergov sindrom javljaju se na strani lezije a sa suprot-ne strane razvijaju se hemipareza i poremeaj senzibiliteta. Jednostrani bol u nuhalnom predelu esto prethodi razvoju neurolokih ispada kod hemimedularne ishemije.

U etiologiji hemimedularnog sindroma najei su in-farkti, tumori ili zapaljenski procesi. S obzirom na snabdeva-nje krvlju dorzolateralnih i medijalnih delova medule iz razli-itih krvnih sudova, ovaj sindrom se karakterie simultanim javljanjem ishemikih lezija u oba podruja. Hemimedularna infarkcija se najee smatra za posledicu aterosklerotine okluzije vertebralne arterije, a prikazani su i veoma retki slu-ajevi uzrone disekcije ove arterije (51-53).

Za razliku od prethodno opisanih klasinih ukrtenih sindroma modanog stable, interpretacija Schmidtovog sin-droma (ipsilateralno oteenje lobanjskih ivaca IX, X, XI, XII udrueno sa kontralateralnom hemiparezom) i Vernetovog sindroma (ipsilateralna lezija nn. IX, X, XI sa kontralateral-nom hemiparezom) je problematina. Analiza istorijskih opi-sa i savremena istraivanja ukazuju da se radi o ekstracere-bralnom oteenju vie kranijumskih ivaca, bez oteenja modanog stabla, tj. da ovi entiteti zapravo ne postoje kao al-terni sindromi (2, 54).

Smatra se da je kliniki znaaj veine ukrtenih sin-droma modanog stabla, izuzev Wallenbergovog sindroma, danas ogranien uglavnom na neuroloke centre (2). Ishemija modanog stabla najei je uzrok akutnih oteenja ove strukture. Veina navedenih sindroma je originalno opisana kao posledica infarkta modanog stabla.

Pravilo 4Gates (55) je predloio jednostavan nain za postavlja-

nje dijagnoze i odreivanja lokalizacije oteenja modanog stabla.

1. Postoje 4 strukture u srednjoj liniji koje poinju sa slovom MMotorni put: kontralateralna slabostMedijalni lemniskus (kontralateralni gubitak vibracij-skog i proprioceptivnog senzibiliteta ruke i noge)Medijalni longitudinalni snop (internukleusna oftal-moloplegija sa iste strane)Motorno jedro lobanjskog ivca (ipsilateralni gubitak funkcije zahvaenog nerva)

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2. Postoje 4 strukture sa lateralnim poloajem koje poinju slovom SSpinocerebelarni putSpinotalamiki put (kontralateralna izmena senzibili-teta za bol i temperaturu ruke i noge)Senzitivno jedro n V (ipsilateralna izmena senzibilite-ta za bol i temperaturu lica)Simpatiki put (ipsilateralni Hornerov sindrom)

3. U produenoj moini su 4 ivca, u ponsu su 4 i iznad mosta su 4 (2 su u srednjem mozgu)

4. U srednjoj liniji su 4 motorna jedra n.III, n.IV, n.VI i n.XII. U lateralnom modanom stablu su jedra n.V, n.VII, n.IX i n.XI.

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