Behçet’s Syndrome and the Nervous System Involvement

  • Ugur Uygunoglu
  • Aksel Siva
Part of the Contemporary Clinical Neuroscience book series (CCNE)


Behçet’s syndrome (BS), a distinct disease with orogenital ulceration and uveitis known as the triple-symptom complex, is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin. The neurological involvement of BS is termed as neuro-Behçet’s syndrome (NBS). Direct neurological involvement of BS may be classified into two forms: (1) parenchymal (p-NBS) and (2) vascular involvement. p-NBS with the rate of 75% among neurological involvements of BS usually presents with an acute-subacute brain stem syndrome. Headache, cranial neuropathy, dysarthria, ataxia, and hemiparesis are the most prominent symptoms. The most common areas affected in p-NBS are the mesodiencephalic junction (MDJ), pons, and medulla oblongata. MDJ lesions tend to extend upward to involve the diencephalic structures and downward to involve the pontobulbar region which is the most common radiological finding observed in p-NBS. The only drug that has been shown to be effective based on the Class IV evidence is infliximab for the treatment of p-NBS.


Behçet’s syndrome Parenchymal neuro-Behçet’s syndrome Cerebral venous sinus thrombosis Bagel Sign Infliximab 


  1. 1.
    Behçet H. [Uber residivierende, aphtöse, durch ein virus verursachte Geschwüre am Mund, am Auge und an den Genitalien.] Dermatol Woschenscr. 1937;105:1152–7 (In German).Google Scholar
  2. 2.
    Criteria for diagnosis of Behçet’s disease. International Study Group for Behçet’s disease. Lancet. 1990;335:1078–80.Google Scholar
  3. 3.
    Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view. Nat Rev Rheumatol. 2018;14(2):107–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Salvarani C, Pipitone N, Catanoso MG, et al. Epidemiology and clinical course of Behçet’s disease in the Reggio Emilia area of Northern Italy: a seventeen-year population-based study. Arthritis Rheum. 2007;57(1):171–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Yurdakul S, Günaydin TY, Tankurt N, Pazarli H, Ozyazgan Y, Yazici H. The prevalence of Behçet’s syndrome in a rural area in northern Turkey. J Rheumatol. 1988;15(5):820–2.PubMedGoogle Scholar
  6. 6.
    Hirohata T, Kuratsune M, Nomura A, Jimi S. Prevalence of Behçet’s syndrome in Hawaii. With particular reference to the comparison of the Japanese in Hawaii and Japan. Hawaii Med J. 1975;34(7):244–6.PubMedGoogle Scholar
  7. 7.
    Papoutsis NG, Abdel-Naser MB, Altenburg A, et al. Prevalence of Adamantiades-Behçet’s disease in Germany and the municipality of Berlin: results of a nationwide survey. Clin Exp Rheumatol. 2006;24(5 Suppl 42):S125.PubMedGoogle Scholar
  8. 8.
    Gül A, Inanç M, Ocal L, Aral O, Koniçe M. Familial aggregation of Behçet’s disease in Turkey. Ann Rheum Dis. 2000;59(8):622–5.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Moore SB, O’Duffy JD. Lack of association between Behçet’s disease and major histocompatibility complex class II antigens in an ethnically diverse North American Caucasoid patient group. J Rheumatol. 1986;13(4):771–3.PubMedGoogle Scholar
  10. 10.
    Yazici H, Akokan G, Yalçin B, Müftüoğlu A. The high prevalence of HLA-B5 in Behçet’s disease. Clin Exp Immunol. 1977;30(2):259–61.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Yazici Y, Yurdakul S, Yazici H. Behçet’s syndrome. Curr Rheumatol Rep. 2010;12:429–35.PubMedCrossRefGoogle Scholar
  12. 12.
    Yurdakul S, Yazici H. Behcet’s syndrome. Best Pract Res Clin Rheumatol. 2008;22(5):793–809.PubMedCrossRefGoogle Scholar
  13. 13.
    Esatoglu SN, Kutlubay Z, Ucar D, Hatemi I, Uygunoglu U, Siva A, et al. Behçet’s syndrome: providing integrated care. J Multidiscip Healthc. 2017;10:309–19.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Mat MC, Goksugur N, Engin B, Yurdakul S, Yazici H. The frequency of scarring after genital ulcers in Behcet’s syndrome: a prospective study. Int J Dermatol. 2006;45(5):554–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Cunningham ET Jr, Tugal-Tutkun I, Khairallah M, Okada AA, Bodaghi B, Zierhut M. Behçet Uveitis. Ocul Immunol Inflamm. 2017;25(1):2–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Akdal G, Toydemir HE, Saatci AO, et al. Characteristics of optic neuropathy in Behçet disease. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e490.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Hatemi I, Hatemi G, Çelik AF. Gastrointestinal involvement in Behçet disease. Rheum Dis Clin N Am. 2018;44(1):45–64.CrossRefGoogle Scholar
  18. 18.
    Bicer A. Musculoskeletal findings in Behcet’s disease. Pathol Res Int. 2012;2012:653806.CrossRefGoogle Scholar
  19. 19.
    Siva A, Kantarci OH, Saip S, et al. Behçet’s disease: diagnostic & prognostic aspects of neurological involvement. J Neurol. 2001;248:95–103.PubMedCrossRefGoogle Scholar
  20. 20.
    Siva A, Esatoglu SN, Uygunoglu U, et al. Could neurological involvement in Behçet’s disease occur atypically? (P5.410). Neurology. 2018;90(15 Supplement).Google Scholar
  21. 21.
    Siva A, Saip S. The spectrum of nervous system involvement in Behcet’s syndrome and its differential diagnosis. J Neurol. 2009;256:513–29.PubMedCrossRefGoogle Scholar
  22. 22.
    Saip S, Akman-Demir G, Siva A. Neuro-Behçet syndrome. Handb Clin Neurol. 2014;121:1703–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Uygunoğlu U, Siva A. Behçet’s syndrome and nervous system involvement. Curr Neurol Neurosci Rep. 2018;18:35.PubMedCrossRefGoogle Scholar
  24. 24.
    Siva A. Common clinical and imaging conditions misdiagnosed as multiple sclerosis: A Current Approach to the Differential Diagnosis of Multiple Sclerosis. Neurol Clin. 2018;36(1):69–117.PubMedCrossRefGoogle Scholar
  25. 25.
    Saruhan-Direskeneli G, Yentür SP, Mutlu M, Shugaiv E, Yesilot N, Kürtüncü M, et al. Intrathecal oligoclonal IgG bands are infrequently found in neuro-Behçet’s disease. Clin Exp Rheumatol. 2013;31(3 Suppl 77):25–7.PubMedGoogle Scholar
  26. 26.
    Kocer N, Islak C, Siva A, et al. CNS involvement in neuro-Behcet’s syndrome: an MR study. Am J Neuroradiol. 1999;20:1015–24.PubMedGoogle Scholar
  27. 27.
    Cohen-Aubart F, Psimaras D, Galanaud D, et al. Cerebral pseudo-tumoral neuro-Behcet: histological demonstration of an inflammatory and vascular disease. Clin Neurol Neurosurg. 2017;161:48–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Uygunoglu U, Zeydan B, Ozguler Y, et al. Myelopathy in Behçet’s disease: the Bagel sign. Ann Neurol. 2017;82:288–98.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee HS, Kim do Y, Shin HY, Choi YC, Kim SM. Spinal cord involvement in Behcet’s disease. Mult Scler. 2016;22:960–3.PubMedCrossRefGoogle Scholar
  30. 30.
    Uygunoglu U, Pasha M, Saip S, Siva A. Recurrent longitudinal extensive transverse myelitis in a neuro-Behcet syndrome treated with infliximab. J Spinal Cord Med. 2015;38:111–4.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Siva A, Özdoğan H, Yazıcı H, Yurdakul S, Yardım M, Akyatan N, et al. Headache, neuro-psychiatric and computerized tomography findings in Behçet’s syndrome. In: Lehner T, Barnes CG, editors. Recent advances in Behçet’s disease. London: Royal Society of Medicine Service; 1986. p. 247–54.Google Scholar
  32. 32.
    Gündüz T, Emir Ö, Kürtüncü M, Mutlu M, Tumaç A, Akca S, et al. Cognitive impairment in neuro-Behcet’s disease and multiple sclerosis: a comparative study. Int J Neurosci. 2012;122(11):650–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Aguiar de Sousa D, Mestre T, Ferro JM. Cerebral venous thrombosis in Behçet’s disease: a systematic review. J Neurol. 2011;258(5):719–27.PubMedCrossRefGoogle Scholar
  34. 34.
    Kizilkilic O, Albayram S, Adaletli I, et al. Endovascular treatment of Behçet’s disease-associated intracranial aneurysms: report of two cases and review of the literature. Neuroradiology. 2003;45:328–34.PubMedCrossRefGoogle Scholar
  35. 35.
    Yesilot N, Bahar S, Yilmazer S, Mutlu M, Kurtuncu M, Tuncay R, et al. Cerebral venous thrombosis in Behçet’s disease compared to those associated with other etiologies. J Neurol. 2009;256(7):1134–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Uluduz D, Midi I, Duman T, et al. Behçet’s disease as a causative factor of cerebral venous sinus thrombosis: subgroup analysis of data from the VENOST study. Rheumatology (Oxford). 2019;58(4):600–8. Scholar
  37. 37.
    Uluduz D, Kürtüncü M, Yapıcı Z, et al. Clinical characteristics of pediatric-onset neuro-Behçet disease. Neurology. 2011;77(21):1900–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Shi J, Huang X, Li G, Wang L, Liu J, Xu Y, Zeng X, Zheng W. Cerebral venous sinus thrombosis in Behçet’s disease: a retrospective case-control study. Clin Rheumatol. 2018;37(1):51–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Hamuryudan V, Yurdakul S, Moral F, et al. Pulmonary arterial aneurysms in Behçet’s syndrome: a report of 24 cases. Br J Rheumatol. 1994;33(1):48–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Uygunoglu U, Saip S, Siva A. Chapter 28: Behcet’s syndrome and nervous system involvement. In: Lisak RP, Truong DD, Carroll WM, et al., editors. International neurology, vol. 2016. 2nd ed. Chichester: John Wiley & Sons, Ltd. p. 88–93.Google Scholar
  41. 41.
    Alpsoy E. Behçet’s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol. 2016;43(6):620–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Direskeneli H, Fujita H, Akdis CA. Regulation of TH17 and regulatory T cells in patients with Behçet disease. J Allergy Clin Immunol. 2011;128(3):665–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Davatchi F, Shahram F, Akbarian M, et al. Behçet disease: analysis of 3443 cases. APLAR J Rheumatol. 1997;1:2–5.Google Scholar
  44. 44.
    Zierhut M, Mizuki N, Ohno S, et al. Immunology and functional genomics of Behçet’s disease. Cell Mol Life Sci. 2003;60(9):1903–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Yazıcı H, Fresko I, Yurdakul S. Behçet’s syndrome: disease manifestations, management, and advances in treatment. Nat Clin Pract Rheumatol. 2007;3:151–5.CrossRefGoogle Scholar
  46. 46.
    Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behcet’s disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford). 2012;51(5):887–900.CrossRefGoogle Scholar
  47. 47.
    Marshall SE. Behçet’s disease. Best Pract Res Clin Rheumatol. 2004;18(3):291–311.PubMedCrossRefGoogle Scholar
  48. 48.
    Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet. 2010;42:703–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Hughes T, Coit P, Adler A, et al. Identification of multiple independent susceptibility loci in the HLA region in Behçet’s disease. Nat Genet. 2013;45(3):319–24.PubMedCrossRefGoogle Scholar
  50. 50.
    Direskeneli H. Autoimmunity vs autoinflammation in Behcet’s disease: do we oversimplify a complex disorder? Rheumatology (Oxford). 2006;45(12):1461–5.CrossRefGoogle Scholar
  51. 51.
    Gul A. Behcet’s disease as an autoinflammatory disorder. Curr Drug Targets Inflamm Allergy. 2005;4:81–3.PubMedCrossRefGoogle Scholar
  52. 52.
    Lule S, Colpak AI, Balci-Peynircioglu B, et al. Behçet disease serum is immunoreactive to neurofilament medium which share common epitopes to bacterial HSP-65, a putative trigger. J Autoimmun. 2017;84:87–96.PubMedCrossRefGoogle Scholar
  53. 53.
    Gül A, Tugal-Tutkun I, Dinarello CA, et al. Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet’s disease: an open-label pilot study. Ann Rheum Dis. 2012;71:563–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum. 2011;41:61–70.PubMedCrossRefGoogle Scholar
  55. 55.
    Addimanda O, Pipitone N, Pazzola G, Salvarani C. Tocilizumab for severe refractory neuro-Behçet: three cases IL-6 blockade in neuro-Behçet. Semin Arthritis Rheum. 2015;44:472–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Deroux A, Chiquet C, Bouillet L. Tocilizumab in severe and refractory Behcet’s disease: four cases and literature review. Semin Arthritis Rheum. 2016;45:733–7.PubMedCrossRefGoogle Scholar
  57. 57.
    McGonagle D, Aydin SZ, Gül A, Mahr A, Direskeneli H. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol. 2015;11:731–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11.PubMedCrossRefGoogle Scholar
  59. 59.
    Neves FS, Spiller F. Possible mechanisms of neutrophil activation in Behçet’s disease. Int Immunopharmacol. 2013;17(4):1206–10.PubMedCrossRefGoogle Scholar
  60. 60.
    Ergun T, Gurbuz O, Harvell J, Jorizzo J, White W. The histopathology of pathergy: a chronologic study of skin hyperreactivity in Behcet’s disease. Int J Dermatol. 1998;37:929–33.PubMedCrossRefGoogle Scholar
  61. 61.
    Hirohata S, Isshi K, Oguchi H, et al. Cerebrospinal fluid interleukin-6 in progressive neuro-Behçet s syndrome. Clin Immunol Immunopathol. 1997;82(1):12–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Akman-Demir G, Tuzun E, Icoz S, et al. Interleukin-6 in neuro-Behçet s disease: association with disease subsets and long-term outcome. Cytokine. 2008b;44(3):373–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Hirohata S, Kikuchi H. Changes in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet’s disease. Intern Med. 2012a;51(24):3359–65.PubMedCrossRefGoogle Scholar
  64. 64.
    Aldinucci A, Bonechi E, Biagioli T, et al. CSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behçet from multiple sclerosis. Ann Clin Transl Neurol. 2018;5(4):493–8.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Belghith M, Bahrini K, Kchaou M, Maghrebi O, Belal S, Barbouche MR. Cerebrospinal fluid IL-10 as an early stage discriminative marker between multiple sclerosis and neuro-Behçet disease. Cytokine. 2018;108:160–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Kalra S, Silman A, Akman-Demir G, et al. Diagnosis and management of neuro-Behcet’s disease: international consensus recommendations. J Neurol. 2014;261:1662–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. 2009;8:192–204.PubMedCrossRefGoogle Scholar
  68. 68.
    Zeydan B, Uygunoglu U, Saip S, et al. Infliximab is a plausible alternative for neurologic complications of Behçet disease. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e258.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ozguler Y, Leccese P, Christensen R, et al. Management of major organ involvement of Behçet’s syndrome: a systematic review for update of the EULAR recommendations. Rheumatology (Oxford). 2018;57(12):2200–12.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ugur Uygunoglu
    • 1
  • Aksel Siva
    • 1
  1. 1.Istanbul University, Cerrahpaşa School of Medicine, Department of NeurologyIstanbulTurkey

Personalised recommendations