Yorgunluk (fatique) semptomlu multipl skleroz hastalarında sitokinlerin  hipotalomo-pituiter-adrenal aks, kortizol, acth ve diğer melanokortinlerle ilişkisinin  değerlendirilmesi
The evaluation of the relationship between cytokines and hypothalamo-pituitary-adrenal axis, cortisol, acth and other melanocortines in multiple sclerosis patients with fatigue symptoms
Yazar: FATMA ZENGİN
Danışman: DOÇ. DR. AYLİN AKÇALI
Gaziantep Üniversitesi / Tıp Fakültesi / Nöroloji Ana Bilim Dalı
Derece: Tıpta Uzmanlık, 2015
Konu: Nöroloji = Neurology
Dizin: Adrenokortikotropik hormon = Adrenocorticotropic hormone ; Genler = Genes ; Hidrokortizon = Hydrocortisone ; Hipotalamo hipofizeal sistem = Hypothalamo hypophyseal system ; Multipl skleroz = Multiple sclerosis ; Sitokinler = Cytokines ; Yorgunluk = Fatigue ; Ölçekler = Scales

Özet:
Multipl Skleroz (MS), genellikle genç erişkin (20-40) yaş grubunu etkileyen merkezi sinir sisteminin (MSS) beyaz cevherinin ilerleyici kronik inflamatuar  demiyelinizan bir hastalığıdır. Yorgunluk, hastaların büyük bir kısmını etkileyen bir belirtidir. MS'teki yorgunluğun nedeni  tam olarak bilinmemektedir. Bu çalışmada Fatigue  Severity  Scale (FSS) ve Neurological Fatigue Index-Multiple Sclerosis (NFI-MS) ölçeklerini kullanarak MS hastalarında yorgunluk durumunu belirlemeyi, FSS ölçeğine göre yorgunluk olan ve yorgunluk olmayan olarak sınıflandırdığımız MS hastalarında serum sitokinlerinin hipotalamo-pituiter-adrenal (HPA) aks, kortizol, ACTH ve diğer melanokortinlerle ilişkisini değerlendirmeyi amaçladık. 
Çalışmaya Gaziantep Üniversitesi Tıp Fakültesi Nöroloji Bilim Dalı'nda RRMS tanısıyla takip edilen 54 (29 kadın, 25 erkek) relapsing remiting, 26 (13 kadın,13 erkek) sağlıklı kontrol dahil edildi. Hastaların 26'sında yorgunluk semptomu var iken (%48,1), 28'sında yorgunluk tespit edilmedi (%51,9). Çalışmamızdan elde edilen sonuçlara göre FSS skoru ile NFI-MS Özet, NFI-MS 1, NFI-MS 2, NFI-MS 3 ve NFI-MS 4 skorları arasında pozitif korelasyon bulundu (her biri için p<0,01). Proinflamatuar sitokinlerden IL-1β ve TNF-α düzeyleri hasta ve kontrol grubunda farklı bulunmadı  (p=0,09, p=0,70). Anti inflamatuvar bir sitokin olan IL-35 düzeyi MS hastalarında anlamlı düzeyde yüksek saptandı (p<0,01). IL-35 açısından yorgunluk olan ve yorgunluk olmayanlar arasında fark yoktu (p=0,46). ACTH, kortizol, α-MSH ise MS grubunda anlamlı dercede (sırasıyla p=0,02, p<0,01, p<0,01)  yüksekti ancak yorgunluk ile ilişkili bulunmadı. Corticotropin-like intermediate lobe peptide (CLIP) düzeyi, MS'de ilk kez bizim çalışmamızda değerlendirilmiştir ve hastalarda kontrole göre anlamlı derecede düşük saptandı (p<0,01). Hastalarda HPA aks hormonları ve sitokin düzeylerininin ilişkisini incelediğimizde; sadece TNF-α ile γ-MSH arasında (p<0,01) ve IL-1β ile β-MSH arasında pozitif korelasyon vardı. 
Sonuç olarak, MS'de yorgunluğu değerlendirmede NFI-MS Özet ölçek de en az FSS skorlaması kadar duyarlıdır. HPA aksı MS hastalarında hiperaktiftir ancak yorgunlukla ve sitokin düzeyleri ile ilişkili bulunmamıştır. IL-35'in MS hastalarındaki yüksekliği hastalık patofizyolojisinde rolü açısından önemli bir role sahip olabileceğini ve yeni tedaviler açısından göz önüne alınabileceğini düşündürmektedir. 

Anahtar kelimeler: Multipl Skleroz, yorgunluk, Hipotalamo-Pituiter-Adrenal Aks

Abstract:
Multiple Sclerosis (MS), is a chronic inflammatory demyelinating disorder affecting the white matter in the central nervous system (CNS), seen usually among young adults (20-40). Fatigue is an important symptom that affects a wide patient population. The reason for fatigue seen in MS patients is still not well-known. 
In this stduy, we aim to detect fatigue analysis in MS patients by using the Fatigue Severity Scale (FSS) and the Neurological Fatigue Index-Multiple Sclerosis (NFI-MS) and also to evaluate the relationship between serum cytokines and hypothalamo-pituitary-adrenal axis, cortisol, ACTH and other melanocortines in MS patients where we divided the patients into 2 groups (fatigue or non-fatigue) using FSS scale. 54 (29 women, 25 men) relapsing remiting multiple sclerosis patients diagnosed and followed by department of Neurology at Gaziantep University Faculty of Medicine and 26 (13 women, 13 men) healty people are involved in the study. 26 (48,1%) of the patients had fatigue symtoms and 28 (51,9 %) of Multiple Sclerosis (MS), is a chronic inflammatory demyelinating disorder affecting the white matter in the central nervous system (CNS), seen usually among young adults (20-40). Fatigue is an important symptom that affects a wide patient population. The reason for fatigue seen in MS patients is still not well-known. 
In this stduy, we aim to detect fatigue analysis in MS patients by using the Fatigue Severity Scale (FSS) and the Neurological Fatigue Index-Multiple Sclerosis (NFI-MS) and also to evaluate the relationship between serum cytokines and hypothalamo-pituitary-adrenal axis, cortisol, ACTH and other melanocortines in MS patients where we divided the patients into 2 groups (fatigue or non-fatigue) using FSS scale. 54 (29 women, 25 men) relapsing remiting multiple sclerosis patients diagnosed and followed by department of Neurology at Gaziantep University Faculty of Medicine and 26 (13 women, 13 men) healty people are involved in the study. 26 (48,1%) of the patients had fatigue symtoms and 28 (51,9 %) of them didn't have any fatigue symptom. 
The results of the study showed that there is a positive correlation between FSS and NFI-MS summary, NFI-MS 1, NFI-MS2, NFI-MS 3, NFI-MS4 (p value < 0.01 for both groups). There weren't any difference in the IL-1β and TNF-α (proinflammatory cytokines) levels both in the patient and control groups (p=0.09, p=0.70). As an antiinflammatory cytokine, IL-35 level were significantly higher in MS patients (p<0.01). But IL-35 levels were not different concerning to fatigue and non-fatigue groups (p=0.46). ACTH, cortisol, α-MSH were significantly higher in MS group compared to control group (respectfully p=0.02, p<0.01, p<0.01)  but a relationship with fatigue couldn't be found. Corticotropin-like intermediate lobe peptide (CLIP) levels in MS were evaluated for the first time in our study and significantly lower in patients compared to control group (p<0.01). When investigating the relationship between HPA axis hormones and cytokine levels; a positive correlation was observed only between TNF- α and γ-MSH (p<0.01) and IL-1β and β-MSH. ,
In conclusion, NFI-MS summary is as sensitive as FSS when evaluating fatigue in MS patients.  HPA axis is hyperactive in  MS patients but a relationship between fatigue and cytokine levels couldn't be established. The fact that the higher evaluation of IL-35 in MS patients could be an important sign in the disease patophysiology and could be taken account while concerning new therapies. 
Key words: Multiple Sclerosis, Fatigue, Hypotalamo-Pituiary-Adrenal Axis                                                                                                                                                                                 
them didn't have any fatigue symptom. 
The results of the study showed that there is a positive correlation between FSS and NFI-MS summary, NFI-MS 1, NFI-MS2, NFI-MS 3, NFI-MS4 (p value < 0.01 for both groups). There weren't any difference in the IL-1β and TNF-α (proinflammatory cytokines) levels both in the patient and control groups (p=0.09, p=0.70). As an antiinflammatory cytokine, IL-35 level were significantly higher in MS patients (p<0.01). But IL-35 levels were not different concerning to fatigue and non-fatigue groups (p=0.46). ACTH, cortisol, α-MSH were significantly higher in MS group compared to control group (respectfully p=0.02, p<0.01, p<0.01)  but a relationship with fatigue couldn't be found. Corticotropin-like intermediate lobe peptide (CLIP) levels in MS were evaluated for the first time in our study and significantly lower in patients compared to control group (p<0.01). When investigating the relationship between HPA axis hormones and cytokine levels; a positive correlation was observed only between TNF- α and γ-MSH (p<0.01) and IL-1β and β-MSH. 
In conclusion, NFI-MS summary is as sensitive as FSS when evaluating fatigue in MS patients.  HPA axis is hyperactive in  MS patients but a relationship between fatigue and cytokine levels couldn't be established. The fact that the higher evaluation of IL-35 in MS patients could be an important sign in the disease patophysiology and could be taken account while concerning new therapies. 
Key words: Multiple Sclerosis, Fatigue, Hypotalamo-Pituiary-Adrenal Axis