Neuropsychic manifestations in the Kyrgyz cohort of patients with systemic lupus erythematosus

The aim of the investigation was to study neuropsychic manifestations (NPM) of systemic lupus erythematosus (SLE) in the Kyrgyz cohort of patients.
Material and methods. The prospective study included 460 patients with a reliable diagnosis of SLE, verified according to the diagnostic criteria ACR (1997) and SLICC (2012), observed in the clinic of the Academician M. Mirrakhimov National Center of Cardiology and Therapy from january 2012 to december 2017. Signs of nervous system damage were revealed in 103 (22.39%) of 460 patients with SLE. Classification criteria of ACR (1999) were used to assess neuropsychic manifestations of SLE, which were diagnosed by the psychiatrist according to ICD-10. Cognitive disorders were detected by a psychologist using a specific test Mini-Mental State Examination (MMSE; mini-scheme study of the mental state of the patient).

Results and discussion. Various signs of NPM SLE were revealed in 103 (22.39%) of 460 patients with SLE. Groups of patients with and without NPM SLE at the beginning of the study were comparable in age, time from the appearance of the first signs of SLE to the verification of the diagnosis and the value of the SLEDAI-2K index (p>0.05). Acute variant of SLE course was significantly associated with NPM SLE. The acute course of SLE was observed in 56 (54.38%) of the 103 patients with NPM SLE and 109 (30.53%) of the 357 patients without NPM SLE [odds ratio (OR) 2.71, 95% confidence interval (CI) of 1.73–4.24; p<0.001]. Subacute and chronic course of the disease was diagnosed in a similar number of patients with NPM SLE – 24 (23.30%) and without NSAIDS – 23 (23.33%) (OR 5.75 95% CI 3.54–9.34; p<0.001). In the majority of patients the central nervous system (CNS) lesions prevailed. It was present in 71 (68.93%) patients, peripheral nervous system (PNS) pathology was less frequent and revealed in 32 (31.07%) of 103 cases, and 4 (3.88%) patients had combined CNS and PNS lesions. One manifestation of NPM SLE was detected in 37 (52.11%) patients, two – in 15 (21.13%), three – in 14 (19.72%) and four – in 5 (7.04%) of 71 patients with CNS lesions. According to the criteria of ACR (1999) in 103 patients 155 different NPM SLE were diagnosed: CNS disorders – in 123 (79.35%) and PNS pathology – in 32 (20.65%). The frequency of focal and diffuse CNS disorders was 61.79% and 38.21%, respectively. Cerebrovascular disease (CVD) was diagnosed most frequently – in 33 (43.42%) of the 76 cases of focal neuropsychiatric CNS disorders. Clinical manifestations of CVD were mainly characterized by discirculatory encephalopathy – in 30 (90.91%), less often – by ischemic stroke in the middle cerebral artery basin on the left – in 2 (6.06%) and transient ischemic attack – in 1 (3.03%) of 33 CVD cases. One manifestation was present in 52.11% of patients with CNS pathology. In other cases, there were more symptoms of its damage. Among the 47 diffuse lesions, neuropsychic disorders of the psychosis type prevailed, the main manifestations of which were visual and auditory hallucinations – in 34 (72.34%) patients.

Conclusion. NPM SLE was identified in 22.39% of patients. Acute variant of SLE and very high activity was associated with NPM SLE. The risk of NPM SLE developing in very high activity of SLE was increased by 5.75 times. In the vast majority of cases in Kyrgyz patients there was CNS involvement (68.93%), twice less – PNS damage (31.07%), combined lesion of PNS and CNS was noted less frequently (3.88%). 47.89% of patients had more than one manifestation of NPM SLE. In most patients with diffuse NPM SLE, psychosis was observed in the form of visual and auditory hallucinations (72.34%), and focal ones were presented by CVD (43.42%), usually in the form of discirculatory encephalopathy (90.91%).

1. Насонов ЕЛ. Клинические рекомендации по ревматологии. 2-е изд., испр. и доп. Москва: ГЭОТАР-Медиа; 2010. C. 429-81 [Nasonov EL. Klinicheskie rekomendatsii po revmatologii [Clinical guidelines for rheumatology]. 2nd ed. Moscow: GEOTAR-Media; 2010. P. 429-81 (In Russ.)].

2. Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol. 2014;10(10):579-96. doi: 10.1038/nrneurol.2014.148 PMid:25201240

3. Zhang X. A study of effects of estrogen receptor and contrasupressor T cell subtype in pathogenesis of SLE. Rev Esp Rheum. 1993;20:420.

4. Magro-Checa C, Zirkzee EJ, Huizinga TW, et al. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs. 2016;76:459-83. doi: 10.1007/s40265-015-0534-3 PMid: 26809245

5. Petri M, Orbai A, Alarson G, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-86. doi: 10.1002/art.34473

6. The American of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;4:599-608. doi: 10.1002/1529-0131(199904)42:4<599::AIDANR2>3.0.CO;2-F

7. Мотовилов АА, Травина ИВ, Проказова НВ. Антитела к нейтральным гликосфинголипидам и ганглиозидам у больных системной красной волчанкой с поражением центральной нервной системы. Клиническая ревматология. 1995;(1):36-8 [Motovilov AA, Travina IV, Prokazova NV. Antibodies to neutral glycosphingolipids and gangliosides in patients with systemic lupus erythematosus with central nervous system damage. Klinicheskaya Revmatologiya. 1995;(1):36-8 (In Russ.)].

8. Насонова ВА, Сперанский АИ. Клинико-иммунологические субтипы системной красной волчанки. В кн.: Современные проблемы ревматологии. 1-й Съезд ревматологов России. Тезисы докладов. Оренбург; 1993. С. 121-2 [Nasonova VA, Speranskii AI. Clinical and immunological subtypes of systemic lupus erythematosus. In: Sovremennye problemy revmatologii. 1-i S"ezd revmatologov Rossii. Tezisy dokladov [Current problems of rheumatology. 1st Congress of Rheumatologists of Russia. Abstracts]. Orenburg; 1993. P. 121-2 (In Russ.)].

9. Пизова НВ, Шилкина НП, Спирин НН. Иммунные повреждения нервной системы при некоторых формах ревматических заболеваний. Журнал неврологии и психиатрии. 2005;(2):73-8 [Pizova NV, Shilkina NP, Spirin NN. Immune damage to the nervous system in some forms of rheumatic diseases. Zhurnal Nevrologii i Psikhiatrii. 2005;(2):73-8 (In Russ.)].

10. Hanly JG. Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol. 2014;10:338-47. doi: 10.1038/nrrheum.2014.15. PMid:24514913

11. Govoni M, Bortoluzzi A, Padovan M, et al. The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J Autoimmun. 2016;74:41-72. doi: 10.1016/j.jaut.2016.06.013. PMID:27427403

12. Stock AD, Wen J, Putterman C. Neuropsychiatric lupus, the blood brain barrier, and the TWEAK/Fn14 pathway. Front Immunol. 2013;4:484. doi: 10.3389/fimmu.2013.00484

13. Fanouriakis A, Pamfil C, Rednic S, et al. Is it primary neuropsychiatric systemic lupus erythematosus? Performance of existing attribution models using physician judgment as the gold standard. Clin Exp Rheumatol. 2016;34(5):910-7. Epub 2016 Jul 26. PMID: 27463840.

14. Ho RC, Thiaghu C, Ong H, et al. A meta-analysis of serum and cerebrospinal fluid autoantibodies in neuropsychiatric systemic lupus erythematosus. Autoimmun Rev. 2016;15:124-38. doi: 10.1016/j.autrev.2015.10.003

15. Kivity S, Agmon-Levin N, Zandman-Goddard G, et al. Neuropsychiatric lupus: a mosaic of clinical presentations. BMC Med. 2015;13:43. doi: 10.1186/s12916-015-0269-8. PMID:25858312

16. Алекберова ЗС, Решетняк ТМ, Рaденска-Лоповок СГ. Васкулопатия у больных системной красной волчанкой с антифосфолипидным синдромом. Терапевтический архив. 1995;(5):41-4 [Alekberova ZS, Reshetnyak TM, RadenskaLopovok SG. Vasculopathy in patients with systemic lupus erythematosus with antiphospholipid syndrome. Terapevticheskii Arkhiv. 1995;(5):41-4 (In Russ.)].

17. Hirohata S, Sakuma Y, Matsueda Y, et al. Role of serum autoantibodies in blood brain barrier damages in neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol. 2018;24. PMID: 29846157.

18. Cohen D, Rijnink EC, Nabuurs RJ, et al. Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology (Oxford). 2017;56(1):77-86. doi: 10.1093/rheumatology/kew341. Epub 2016 Oct 25.

19. Иванова ММ, Близнюк ОИ, Щекутьев ГА, Пушкова ОВ. Диагностика поражения центральной нервной системы у больных системной красной волчанкой. Клиническая ревматология. 1991;(4):6-8 [Ivanova MM, Bliznyuk OI, Shchekut'ev GA, Pushkova OV. Diagnosis of central nervous system lesions in patients with systemic lupus erythematosus. Klinicheskaya Revmatologiya. 1991;(4):6-8 (In Russ.)].

20. Zirkzee EJ, Steup-Beekman GM, van der Mast RC, et al. Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy. J Rheumatol. 2012;39(11):2118-26. doi: 10.3899/jrheum.120545

21. Vivaldo JF, de Amorim JC, Julio PR, et al. Definition of NPSLE: Does the ACR Nomenclature Still Hold? Front Med (Lausanne). 2018 May 31;5:138. doi: 10.3389/fmed.2018.00138

22. Иванова ММ, Близнюк ОИ, Тодау ФИ, Туманова АА. Поражение центральной нервной системы при системной красной волчанке. Клиническая медицина. 1989;(2):93-7 [Ivanova MM, Bliznyuk OI, Todau FI, Tumanova AA. Central nervous system damage in systemic lupus erythematosus. Klinicheskaya Meditsina. 1989;(2):93-7 (In Russ.)].

23. Hanly JG, Urowitz MB, Sanchez-Guerrero J, et al. Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study. Arthritis Rheum. 2007;56(1):265-73. doi: 10.1002/art.22305

24. Иванова ММ. ЦНС-люпус: проблемы и достижения (результаты 10-летнего – клинико-инструментального исследования). Терапевтический архив. 2001;(6):25-9 [Ivanova MM. CNS-lupus: problems and achievements (results of a 10-year clinical and instrumental study). Terapevticheskii Arkhiv. 2001;(6):25-9 (In Russ.)].

25. Харченко СА, Грехов РА, Сулейманова ГП и др. Психологические особенности больных системной красной волчанкой. Современные проблемы науки и образования. 2015;(5) [Kharchenko SA, Grekhov RA, Suleimanova GP, et al. Psychological features of patients with systemic lupus erythematosus. Sovremennye Problemy Nauki i Obrazovaniya. 2015;(5) (In Russ.)].

26. Hussein MA, Elsabagh YA, Hosny A, Elgendy H. Silent cerebral MRI findings in lupus nephritis patients: is it clinically significamt? J Adv Res. 2017 Nov;20(9):63-7. doi: 10.1016/j.jare.2017.10.011

27. Койлубаева ГМ, Асеева ЕА, Соловьев СК и др. Клинические проявления, варианты течения и исходы системной красной волчанки у жителей Кыргызстана. Научно-практическая ревматология. 2016;54(4):432-41 [Koilubaeva GM, Aseeva EA, Solovyev SK, et al. Clinical mani festations, courses, and outcomes of systemic lupus erythematosus in the dwellers of Kyrgyzstan. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(4):432-41 (In Russ.)]. doi: 10.14412/1995-4484-2016-432-441].

28. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. doi: 10.1002/art.1780400928

29. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288-91.

30. Unterman A, Nolte JE, Boaz M, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. 2011;41(1):1-11. doi: 10.1016/j.semarthrit.2010.08.001

31. Benseler S, Silverman E. Neuropsychiatric involvement in pediatric systemic lupus erythematosus. Lupus. 2007;16:564-71. doi: 10.1177/0961203307078971

32. Popescu A, Kao AH. Neuropsychiatric Systemic Lupus Erythematosus. Curr Neuropharmacol. 2011;9(3):449-57. doi: 10.2174/157015911796557984

33. Brey RL. Neuropsychiatric lupus: clinical and imaging aspects. Bull NYU Hosp Jt Dis. 2007;65(3):194-9.

34. Zirkzee EJ, Huizinga TW, Bollen EL, et al. Mortality in neuropsychiatric systemic lupus erythematosus (NPSLE). Lupus. 2014;23(1):31-8. doi: 10.1177/0961203313512540

35. Dö ndü Üskü daz Cansu, Hava Üskü dar Teke, Gengiz Korkmaz. Survival analysis of Turkish patients with systemic lupus erythematosus: older age of diagnosis affects mortality. Arch Rheumatol. 2017;32(2):141-8. doi: 10.5606/ArchRheumatol.2017.6173

36. Morad CS, Mansour HE, Ibrahim SE, et al. Subclinical neuropsychiatric dysfunctions in female patients with systemic lupus erythematosus. Egyptian Rheumatol Rehabil. 2018;45:49-56. doi: 10.4103/err.err_46_17

37. Ainiala H, Hietaharju A, Loukkola J, et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum. 2001;45(5):419-23. doi: 10.1002/1529-0131(200110)45:5<419::AID-ART360>3.0.CO;2-X

38. Hanly JG. ACR classification criteria for systemic lupus erythematosus: limitations and revisions to neuropsychiatric variables. Lupus. 2004;13(11):861-4. doi: 10.1191/0961203304lu2024oa

39. Birnbaum J, Petri M, Thompson R, et al. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum. 2009;60(11):3378-87. doi: 10.1002/art.24937

40. Barber CE, Leclerc R, Gladman DD, et al. Posterior reversible encephalopathy syndrome: an emerging disease manifestation in systemic lupus erythematosus. Semin Arthritis Rheum. 2011;41(3):353-63. doi: 10.1016/j.semarthrit.2011.07.001

41. Ahn GY, Kim D, Won S, et al. Prevalence, risk factors, and impact on mortality of neuropsychiatric lupus: a prospective, single-center study. Lupus. 2018 Jul;27(8):1338-47. doi: 10.1177/0961203318772021

42. Pego-Reigosa JM, Isenberg DA. Psychosis due to systemic lupus erythematosus: characteristics and long-term outcome of this rare manifestation of the disease. Rheumatology. 2008;47:1498-502. doi: 10.1093/rheumatology/ken260

43. Rowshani AT, Remans P, Rozemuller A, Tak PP. Cerebral vasculitis as a primary manifestation of systemic lupus erythematosus. Ann Rheum Dis. 2005;64:784-6. doi: 10.1136/ard.2004.026542

44. Gerli R, Caponi L, Tincani A, et al. Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: Prospective evaluation in a large cohort of Italian patients. Rheumatology. 2002;41:1357-66. doi: 10.1093/rheumatology/41.12.1357

45. Hermosillo-Romo D, Brey RL. Diagnosis and management of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Best Pract Res Clin Rheumatol. 2002;16(2):229-44. doi: 10.1053/berh.2001.0223

46. Purandare KN, Wagle AC, Parker SR. Psychiatric morbidity in patients with systemic lupus erythematosus. Q J Med. 1999;92:283-6. doi: 10.1093/qjmed/92.5.283

47. Kakati S, Barman B, Ahmed SU, Hussain M. Neurological Manifestations in Systemic Lupus Erythematosus: A Single Centre Study from North East India. J Clin Diagn Res Intern Med Sect. 2017;11(01):0C05-OCO9. doi: 10.7860/JCDR/2017/23773.9280

48. Khajezadeh MA, Zamani G, Moazzami B, et al. Neuropsychiatric Involvement in Juvenile-Onset Systemic Lupus Erythematosus. Neurol Res Int. 2018 May 29:2548142. doi: 10.1155/2018/2548142

49. Szmyrka M, Pokryszko-Dragan A, Slotwinski K, et al. Cognitive impairment, event-related potentials and immunological status in patients with systemic lupus erythematosus. Adv Clin Exp Med. 2018 Jul 2. doi: 10.17219/acem/76711

50. Brey RL, Holliday SL, Saklad AR, et al. Neuropsychiatric syndromes in lupus. Neurology. 2002;58:1214-20. doi: 10.1212/WNL.58.8.1214PMid:11971089

51. Mikdashi J, Handwerger B. Predictors of neuropsychiatric damage systemic lupus erythematosus: data from the Maryland lupus cohort. J Rheumatol. 2004;43:1555-60. doi: 10.1093/rheumatology/keh384

52. Mok CC, Mak A, Chu WP, et al. Long-term survival of southern Chinese patients with systemic lupus erythematosus: a prospective study of all age-groups. Medicine (Baltimore). 2005;84:218-24. doi: 10.1097/01.md.0000170022.44998.d1

53. Whitelaw DA, Spangenberg JJ, Rickman R, et al. Association between the antiphospholipid antibody syndrome and neuropsychological impairment in SLE. Lupus. 1999;8:444-8. doi: 10.1177/096120339900800606

54. Everett CM, Graves TD, Lad S, et al. Aggressive CNS lupus vasculitis in the absence of systemic disease activity. Rheumatology (Oxford). 2008;47:107-9. doi: 10.1093/rheumatology/kem264

55. Johnson RT, Richardson EP. The neurological manifestations of systemic lupus erythematosus. Medicine (Baltimore). 1968;47:337-69. doi: 10.1097/00005792-196807000-00002

56. Kleinig TJ, Koszyca B. Fulminant leucocytoclastic brainstem vasculitis in a patient with otherwise indolent systemic lupus erythematosus. Lupus. 2009;18:486-90. doi: 10.1177/0961203308101548

57. Rizos T, Siegelin M, Hä hnel S, et al. Fulminant onset of cerebral immunocomplex vasculitis as first manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). Lupus. 2009;18:361-3. doi: 10.1177/0961203308097448

58. Lukjanowcz M, Brzosko M. Myelitis in the course of systemic lupus erythematosus. Polskie Arch Med Wew. 2009;119(1-2):67-72.

59. Krishnan C, Kaplin AI, Deshpande DM, et al. Transverse myelitis: pathogenesis, diagnosis and treatment. Front Biosci. 2004;9:1483-99. doi: 10.2741/1351

60. Toledano P, Orueta R, Rodriguez-Pinto I, et al. Peripheral nervous system involvement in systemic lupus erythematosus: Prevalence, clinical and immunological characteristics, treatment and outcome of a large cohort from a single centre. Autoimmun Rev. 2017 Jul;16(7):750-5. doi: 10.1016/j.autrev.2017.05.011

61. Saigal R, Bhargav R, Goyal L, et al. Peripheral Neuropathy in Systemic Lupus Erythematosus: Clinical and Electrophysiological Properties and their Association with Disease Activity Parameters. J Assoc Physicians India. 2015 Dec;63(12):15-9.

62. Huynh C, Ho SL, Fong KY, et al. Peripheral neuropathy in systemic lupus erythematosus. J Clin Neurophysiol. 1999;16(2):164-8. doi: 10.1097/00004691-199903000-00010

63. Лайсэк РП, Левинсон АИ. Невропатии при заболеваниях соединительной ткани. Заболевания периферической нервной системы. Москва: Медицина; 1987. 280 с. [Laisek RP, Levinson AI. Nevropatii pri zabolevaniyakh soedinitel'noi tkani. Zabolevaniya perifericheskoi nervnoi sistemy [Neuropathy in connective tissue diseases. Peripheral nervous system diseases]. Moscow: Meditsina; 1987. 280 p. (In Russ.)].

64. Mondelli M, Romano C, Porta P, Rossi A. Electrophysiological evidence of «nerve entrapment syndromes» and subclinical peripheral neuropathy in progressive systemic sclerosis. J Neurol.