Journal of Immunology Research

Journal of Immunology Research / 2019 / Article

Research Article | Open Access

Volume 2019 |Article ID 7371458 | https://doi.org/10.1155/2019/7371458

Dong Yan, JinJing Liu, Yuehua Zhang, Wei Yuan, Yan Xu, Jing Shi, Chaoran Li, Yining Wang, Linyi Peng, Yunjiao Yang, Jiaxin Zhou, Di Wu, Zhichun Liu, Xiaofeng Zeng, Fengchun Zhang, Wenjie Zheng, Yan Zhao, "The Clinical Features and Risk Factors of Parenchymal Neuro-Behcet’s Disease", Journal of Immunology Research, vol. 2019, Article ID 7371458, 7 pages, 2019. https://doi.org/10.1155/2019/7371458

The Clinical Features and Risk Factors of Parenchymal Neuro-Behcet’s Disease

Academic Editor: Eirini Rigopoulou
Received08 Dec 2018
Revised03 Jul 2019
Accepted20 Jul 2019
Published12 Sep 2019

Abstract

To investigate the clinical features of parenchymal neuro-Behcet’s disease (p-NBD), we retrospectively reviewed the medical records of 1009 BD patients admitted to Peking Union Medical College Hospital from 2000 to 2016. Forty-two patients (25 males and 17 females) with p-NBD and eighty-four age- and sex-matched BD patients without neurological involvement who were served as controls were enrolled. Neurological onset was concomitant with the onset of BD in six cases (14.3%). Pyramidal signs (50.0%) and headache (33.3%) were the most common manifestations. On MRI, the lesions were mainly in the midline structures and hyperintense in the T2-weighted image. The most common lesion was the brainstem (54.8%). Spinal cord involvement was observed in five cases, four of which with cervical cord involvement. Multifocal lesions were observed in 13 patients. Ocular involvement was more prevalent in p-NBD (35.7%) (, , 95% -5.44) compared with controls. All patients received corticosteroids and immunosuppressants, mainly cyclophosphamide (39/42). Six patients with severe/refractory condition received biological agents and achieved response measured by decreased Rankin score (). With a median follow-up of 28 months, 22 patients (61.1%) achieved clinical improvements, while 10 (27.8%) relapsed and 4 died (mortality rate 11.1%). p-NBD is a rare yet disabling and life-threatening complication of BD. Ocular involvement is a risk factor for p-NBD. Promptly aggressive treatment is essential for improving prognosis, and biological agents might be a promising approach for severe/refractory p-NBD.

1. Introduction

Behcet’s disease (BD) is a multisystem inflammatory disease with unknown etiology. Central nervous system involvement in BD, the so-called neuro-Behcet’s disease (NBD), is one of its most serious complications and an important cause of morbidity and mortality [1]. The frequency of NBD greatly varies from 1.3% [2] to 59% [3], due to differences in ethnic, geographical distribution, and study designs. It can be caused by either primary neural parenchymal lesions or secondary to vascular involvement. The former is called parenchymal NBD (p-NBD) and represents the majority of NBD [46]. According to the site of the lesions, p-NBD can be classified as multifocal/diffuse, brainstem, spinal cord, cerebral, asymptomatic, and optic neuropathy [7]. It may present with numerous manifestations, such as pyramidal signs, headache, and dysarthria, consistent with the site of the lesions. The 10-year mortality of p-NBD is 10% [7], while nonparenchymal NBD (non-p-NBD) often tends to recover well with appropriate and prompt treatment.

To date, p-NBD has been reported in some other countries [4, 812] and the clinical features of Chinese p-NBD patients have not been characterized by clarity. To address this issue, we conducted a retrospective study on hospitalized BD patients and identified the patients with p-NBD. We summarized the clinical characteristics, the cerebrospinal fluid (CSF) tests, magnetic resonance imaging (MRI) findings, treatment, and prognosis and further explored the potential risk factors for p-NBD in order to make an early diagnosis and improve prognosis.

2. Materials and Methods

2.1. Patients

BD patients who were admitted to Peking Union Medical College Hospital from 2000 to 2016 were retrospectively enrolled. All patients fulfilled 1990 International Study Group (ISG) BD criteria [13] or new International Criteria for BD (ICBD) [14]. The diagnosis of neurological involvement was based on the abnormalities on neurological examination, CSF analysis, or neuroradiological examinations. The diagnosis was made by two rheumatology experts and two neurology experts according to the criteria of the 2014 International Consensus on NBD [15]. We chose the modified Rankin score to assess the disability status of NBD patients [16]. Clinical data including demographics, clinical features, laboratory tests, imaging, treatment, and outcome were retrospectively extracted from the medical records.

The courses of p-NBD were classified as the acute course (defined as acute onset of neurological symptoms and signs lasting >24 hours), chronic progressive course, and silent course (defined as detection of abnormal findings on neurological examination in cases who did not have any neurological complaints) [11].

We randomly matched eighty-four BD patients (at 1 : 2 ratio) without neurological involvement by sex and age as the control group to identify the risk factors in p-NBD. The study was reviewed and approved by the institutional ethics review board of Peking Union Medical College Hospital in accordance with the Declaration of Helsinki. Given the study was based on the review of medical records, written informed consent was waived. The patient’s records/information was anonymized and deidentified prior to the analysis.

2.2. Statistical Analysis

Statistical analysis was performed with SPSS version 21.0 (IBM Inc., Armonk, USA). Frequencies and percentages were used for categorical variables. (SD) was used to express quantitative variables of the normal distribution, while median and range were used for abnormal distribution. The continuous variables were analyzed by -test or Mann–Whitney test, as appropriate. A value of was regarded as indicating statistical significance.

3. Result

3.1. Epidemiology

Of 1009 hospitalized BD patients in the same academic hospital during the same period, NBD was documented in 62 patients (6.1%), and a total of 42 patients had parenchymal involvement (4.2%, 25 males and 17 females). In patients with p-NBD, the male/female ratio was 1.47 : 1. Their age at onset of BD was years old, and age at neurological onset was years old. Most of the patients suffered neurological symptoms after other initial systemic symptoms of BD in the median interval of 2 months (range from 0 to 18 months). Neurological onset was concomitant with the onset of BD in six cases (14.3%). Additionally, of the 20 NBD patients but without p-NBD in our cohort, 17 patients were presented with cerebral venous sinus thrombosis (CVST) and the other three patients had peripheral nervous system involvement.

3.2. BD Manifestations

In patients with p-NBD, oral ulceration presented in all, followed by genital ulcers (64.3%), skin lesions (45.2%) (including pseudofolliculitis, erythema nodosa, or positive pathergy test), ocular involvement (35.7%) (including uveitis, retinal vasculitis, and scleritis), arthritis (21.4%), vascular involvement (14.3%) (deep vein thrombosis in 5 cases and pulmonary embolism in 1 case), and gastrointestinal involvement (7.1%) (all presented as terminal ileum ulceration). Only one case had mitral valve lesion (Table 1).


Clinical manifestations (%)

Oral ulcers42 (100%)
Genital ulcers27 (64.3%)
Skin lesions19 (45.2%)
Ocular involvement15 (35.7%)
Arthritis9 (21.4%)
Vascular involvement6 (14.3%)
Gastrointestinal lesions3 (7.1%)

4. Neurological Features

4.1. Clinical Features

Seventeen patients (40.5%) presented with an acute onset and 24 patients (57.1%) had a progressive course, while one case showed a silent course. The most common involved sites of p-NBD were brainstem (23/42, 54.8%) and hemisphere (22/42, 52.4%). Five cases (11.9%) had spinal cord involvement, in which 4 had cervical cord involved and one had thoracic cord involved. 13 cases (31.0%) suffered from multiple lesions (Table 2). The diagnosis of p-NBD in 3 cases was based on the typical neurological symptoms and signs, abnormal CSF examinations, and electroencephalogram, though neuroradiological findings were normal. In addition to BD, no other diagnosis could better explain the clinical picture.


Neurological lesions (%)

Brainstem involvement23 (54.8%)
 Isolated brainstem10 (23.8%)
 Brainstem+13 (31.0%)
Hemicerebrum involvement22 (52.4%)
Spinal cord involvement5 (11.9%)
 Cervical cord4 (9.5%)
 Thoracic cord1 (2.4%)
Cerebellum4 (9.5%)
Localization not possible3 (7.1%)
More than two sites13 (31.0%)

These 3 patients showed only neurological clinical symptoms and abnormal CSF examinations, and in all these 3 cases, MRI was normal.

Patients with p-NBD had a variety of neurological signs and symptoms (Table 3). The most common clinical symptoms were pyramidal signs (50.0%), followed by headache and psychological and behavioral change (each 33.3%). Irritating cough (31%), myasthenia (28.6%), dysarthria (26.2%), and movement disorder (21.4%) were also commonly observed. Some symptoms were less frequently noticed such as urinary retention, visual loss, cognitive dysfunction, epilepsy, conscious disturbance, ataxia, and hemiplegia.


Neurological symptoms (%)

Pyramidal sign21 (50.0%)
Headache14 (33.3%)
Psychological and behavioral change14 (33.3%)
Irritating cough13 (31.0%)
Myasthenia12 (28.6%)
Dysarthria11 (26.2%)
Movement disorder9 (21.4%)
Urinary retention7 (16.7%)
Visual loss6 (14.3%)
Cognitive dysfunction5 (11.9%)
Epilepsy4 (9.5%)
Conscious disturbance4 (9.5%)
Ataxia4 (9.5%)
Hemiplegia3 (7.1%)

4.2. Neurological Imaging

All patients received neurological MRI examination. Thirty-nine cases presented with parenchymal lesions. Of those with parenchymal impairment, the brainstem, the periventricular area, the centrum semiovale, and the spinal cord were involved in twenty-two (22/42), thirteen (13/42), eight (8/42), and five patients (5/42), respectively. Typically, the lesions were hyperintense on T2-weighted MRI and hypointense on T1-weighted sequences. Only one patient had brainstem atrophy, whose interleukin-6 (IL-6) level in CSF was elevated (78.5 pg/mL).

4.3. CSF Analysis

CSF analysis was performed in 40 patients. The opening pressure was increased in 8 cases (20%), ranging from 195 to 270 mmH2O. CSF protein was mildly elevated in 22 cases, with a mean level of g/L. All cases showed normal chloride and glucose level of CSF. Pleocytosis was shown in 11 cases, and assessment of cytological examination of CSF was conducted in 20 patients. Nine cases showed mixed pictures with lymphocyte predominance, and two cases showed mainly neutrophil picture. Both CSF and serum protein electrophoresis for oligoclonal bands (OCB) were performed in 21 cases. Seven cases were positive in CSF while negative in serum (33.3%). CSF cytokine levels were tested in three cases during acute attacks. Elevated IL-6 and tumor necrosis factor (TNF-α) levels were detected in two patients, respectively.

4.4. Laboratory Examinations

Erythrocyte sedimentation rate (ESR) was significantly elevated in 45.2% (19/42) with the median level of 15 (ranged 0-85 mm/h). While hypersensitive C-reactive protein (hs-CRP) levels elevated in 50% (21/42) with the median level of 3.0 (0.14-124 mg/L). All patients but one showed low-titer antinuclear antibody (ANA) (1 : 160).

4.5. Comparison between Acute and Progressive p-NBD

The data showed no statistical significance in clinical features, sites of neurological involvement, CSF tests, and laboratory examinations between acute and progressive p-NBD patients () (data not shown).

4.6. Comparison with BD without Neurological Involvement

Eighty-four age- and gender-matched BD patients without neurological involvement were randomly selected at 1 : 2 ratio and served as the control group. Compared with the controls, the prevalence of ocular involvement (including uveitis, retinal vasculitis, and scleritis) was significantly higher in p-NBD (35.7%) (, , 95% -5.44) (Table 4). The average interval from the onset of ocular to neurological symptoms was months. Fifteen cases had ocular involvement, among whom six cases were treated with cyclosporine A (CsA) before the onset of neurological symptoms with the dosage ranging from 75 mg bid to 150 mg bid for () months. Some other clinical manifestations, ESR, and CRP showed no statistical significance.


Parametersp-NBD ()Controls¥ () valueOR (95% CI)

Age (years, )0.6011.01 (0.98-1.04)
Gender (F/M)25/1750/341.000
Clinical features of BD
 Oral ulceration42 (100%)84 (100%)1.000
 Genital ulceration27 (64.3%)61 (72.6%)0.3370.68 (0.31-1.50)
 Skin lesions19 (45.2%)40 (47.6%)0.8010.91 (0.43-1.91)
 Gastrointestinal lesions3 (7.1%)17 (20.2%)0.0580.30 (0.08-1.10)
 Ocular involvement·15 (35.7%)16 (19.0%)0.041||2.36 (1.03-5.44)
 Vascular involvement6 (14.3%)10 (11.9%)0.7051.23 (0.42-3.66)
Laboratory tests
 ESR (mm/h, median and range)15 (0-85)11 (1-80)0.0721.01 (0.99-1.03)
 CRP (mg/L, median and range)3.0 (0.14-124)3.3 (0.13-104)0.9951.00 (0.98-1.02)

OR = odds ratio; CI = confidential interval. Values are the number (percentage) unless otherwise indicated. ¥Eighty-four age- and gender-matched BD patients without neurological involvement were served as control. ·Ocular involvement includes uveitis, retinal vasculitis, and scleritis. ||.
4.7. Treatment and Outcome

All p-NBD patients received corticosteroids (as  mg/kg/d or the equivalent dosage of other corticosteroids) and 23 patients (54.8%) received methylprednisolone pulse therapy. A total of forty patients were treated with immunosuppressants, in which cyclophosphamide (CTX) 39 cases, CsA 4 cases, azathioprine (AZA) 3 cases, methotrexate (MTX) 1 case, and thalidomide 1 case. Nine patients received more than one immunosuppressant. Intrathecal injection of dexamethasone 10 mg and methotrexate 10 mg was administrated in 28 patients.

Six severe and/or refractory p-NBD patients, with a poor baseline disability status (mean Rankin score was 4), received biological agents, including infliximab (IFX) in 4 cases, tocilizumab (TCZ) in 1 case, and interferon (IFN)-α2a in 1 case (Table 5). After a median follow-up of 21.5 months, all the patients achieved clinical improvements. The Rankin score was significantly decreased to () (). Additionally, follow-up MRI showed the lesions significantly reduced in two of them. Furthermore, the dosage of corticosteroids was tapered from  mg/kg/d to 0-10 mg/d, and immunosuppressants were tapered in number and dosage in 3 (50%) and 6 patients (100%), respectively. No serious adverse events were observed.

(a)

CaseAgeM/FHistory of treatmentClinical manifestations of p-NBD
SymptomsLesion sitesCSF tests

124MGCa CTXPyramidal sign, ataxia, irritating coughBrainstem, cerebellum, spinal cordNormal
245MGCa CTX THDPyramidal sign, dysarthria, irritating coughBrainstem, cerebellumPro 0.46 g/L, normal pressure, and cytological test
335MGCa CTXPyramidal sign, epilepsy, psychological and behavioral change, disturbance of urine, myastheniaBrainstem, hemicerebrum, spinal cordICP 200 mmH2O, WBC 6/L, Pro 1.19 g/L
415MGCb MTXEpilepsy, headacheNot possibleICP 235 mmH2O, normal biochemical and cytological test
536MGCb MTX AZAPsychological and behavioral change, disturbance of urine, myastheniaBrainstem, hemicerebrum, spinal cordWBC 6/L, Pro 0.61 g/L
615FGCa CTX CsADysarthria, irritating cough, psychological and behavioral changeHemicerebrumICP 246 mmH2O, normal biochemical and cytological test

(b)

CaseTreatment of biological agentsFollow-up
Biological agentsDoseCourseDrug combinationSymptomsSide effectsPeriod (months)

1IFX3 mg/kg4 timesGCc CTXImprovedNone31
2IFX5 mg/kg5 timesGCc CTXImproved and ESR/CRP became normalNone12
3IFX3 mg/kg4 timesGCc AZASymptoms and follow-up MRI got improvedNone9
4IFX3 mg/kg5 timesMTXNo more seizuresNone72
5TCZ8 mg/kg10 timesGCc AZASymptoms and follow-up MRI got improvedNone11
6IFN-α2a3 Mu53 monthsGCc CsAImproved and ESR/CRP became normalNone104

GC: glucocorticoid; CTX: cyclophosphamide; THD: thalidomide; MTX: methotrexate; AZA: azathioprine; CsA: cyclosporine A; Pro: protein; ICP: intracranial pressure; WBC: white blood cell. aMethylprednisolone pulse therapy. bAs  mg/kg/d or the equivalent dosage of other corticosteroids. cAs prednisone 5 mg/d-10 mg/d.

Overall, with a median follow-up of 28 months (4 to 156 months), 22 out of 36 patients (61.1%) achieved clinical improvements, including the four patients treated with CsA after the diagnosis of p-NBD. 10 patients (27.8%) relapsed and 4 patients died (the mortality rate was 11.1%). Six patients were lost to follow-up.

5. Discussion

p-NBD accounted for 67.7% of neuro-Behcet’s disease in our cohort, and the proportion and the male predominance (59.5%) was similar to the data reported [11, 12, 17]. The neurological symptoms usually occur after the BD diagnosis is established. However, in 6 patients (14.3%), the neurological manifestations preceded the diagnosis of BD in our series. This emphasizes that rheumatologists and neurologists must be aware of this possible rare cause of neurological symptoms.

As previously reported, the most frequently affected area of p-NBD was the brainstem [4]. Hemicerebrum, spinal cord, and cerebellum can also be involved. Nearly one-third of the patients suffered from multiple lesions. In our study, cervical cord involvement was more common in spinal cord lesions, while previous research has shown that thoracic cord was more susceptible [18]. The difference may be due to different race or study design. The most common initial manifestations of p-NBD were pyramidal signs and headaches, as described in the literature [7]. Psychological and behavioral change showed a high incidence in our study. Atypical symptoms may lead to misdiagnosis.

CSF examination plays an important role in the diagnosis of p-NBD. Our data suggested that most p-NBD patients tend to have normal intracranial pressure and CSF pleocytosis. The pleocytosis pictures of CSF can present as neutrophil-predominant or lymphocyte-predominant depending on the course of the disease [7]. Our data showed a higher CSF-OCB-positive rate in p-NBD than the previous reports [8, 11]. All these CSF-OCB-positive cases in our cohort were in an acute course and with high disease activity. As a previous study showed CSF oligoclonal IgA and IgM may be helpful in monitoring CNS disease activity in NBD [19]. A further study to monitor CSF-OCB in both active and remission periods of p-NBD would be more valuable. Two cases showed high-level proinflammatory cytokines in accordance with active disease. Proinflammatory cytokines such as IL-6 can be markers of disease activity or prognosis [20].

MRI has obvious advantages in displaying small vessel lesions. The most commonly affected site was the midline structure, such as the brainstem. Most lesions in p-NBD were hyperintense on T2-weighted MRI. The previous study indicated that brainstem atrophy, especially in the absence of cortical atrophy, is highly specific to the diagnosis of NBD [21]. Meanwhile, high levels of proinflammatory cytokines, especially IL-6, might be important for the induction of apoptosis of neurons in p-NBD [22]. In our study, one case showed brainstem atrophy on MRI with high-level CSF-IL-6. Given the complexity of the disease, the measurement of a single cytokine does not provide sufficient discrimination to assess the correlation of imaging changes and disease courses [23].

Our data revealed a high frequency of ocular involvement in p-NBD. Ocular involvement, like uveitis, retinitis, and scleritis, is a “warning sign” for predisposition to parenchymal involvement in BD. The recent study from Turkey [9] also showed the significant association between posterior uveitis and p-NBD. The mechanism of this phenomenon has not been clarified. A meta-analysis showed that the risk of developing nervous system involvement was significantly higher among BD patients who used CsA compared with those who did not (, 95% -15.32) [24]. In our cohort, six cases complicated with ocular involvement treated with CsA before the onset of p-NBD and the immunosuppressants were adjusted after the neurological attack. However, four cases received high-dose methylprednisolone pulse therapy followed by oral prednisone plus CsA after the diagnosis of p-NBD, achieved remission, and remained stable during the follow-up.

Glucocorticoids and immunosuppressants are the cornerstones for the management of p-NBD [25]. However, no treatment option for p-NBD has been supported by randomized trials. CTX was the most commonly used immunosuppressant in our study, and some cases required combination therapy with multiple immunosuppressants. Systemic administration combined with intrathecal injection with MTX and/or dexamethasone was also effective. For the severe and/or refractory p-NBD cases, biological therapy achieved clinical and imaging improvement in addition to successfully tapering immunosuppressants, indicating a potential steroid- and immunosuppressant-sparing effect. Recently, there is growing evidence revealing the efficacy of the biological agents, such as TNF-α inhibitors [26], TCZ [27], and IL-1 inhibitor [28], suggesting alternative therapeutic approaches for refractory cases. The international consensus [15] and 2018 EULAR recommendations [25] for p-NBD also recommended anti-TNF therapy to be considered on severe disease as first-line or refractory patients. We assume that earlier and more widespread use of biologics may improve the outcome. We expect more clinical research to confirm this opinion in the future.

In concordance with previous reports, our study showed a poor prognosis in p-NBD. Four patients died from the disease. Early recognition of severe organ involvements is essential for improving prognosis.

Our study presents the clinical characteristics of the largest cohort of Chinese patients over 16 years. It has several limitations. Firstly, since all patients were enrolled from a national referral center, a potential selection bias toward severe cases could not be excluded. Secondly, it was a retrospective study. Given the limited number of cases, we could not clarify the correlation between CsA and the pathogenesis of NBD. A further multicenter case-control study is warranted to overcome these limitations.

6. Conclusions

In summary, the parenchymal neurological involvement is a rare complication of BD with a high morbidity and mortality. It has a male predominance and most commonly involves the brainstem. Ocular involvement is a risk factor for p-NBD. Glucocorticoids and immunosuppressants are the major therapies. Although larger studies are still needed to clarify some issues, as safety and sustained response after discontinuation, biological agents may be a useful alternative choice for p-NBD patients with severe organ damage or refractory to conventional therapy.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors’ Contributions

Dong Yan, JinJing Liu, and Yuehua Zhang contributed equally to this work.

Acknowledgments

We gratefully acknowledge all patients who participated in our study. This work was supported by the National Natural Science Foundation of China (grant numbers 81571598 and 81871299); the National Key Research and Development Program: “Precise Medical Research” (grant number 2016YFC0906201); the CAMS Initiative for Innovative Medicine (grant number 2016-I2M-1013); the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS2017-I2M-1-008); and the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2017YFC0907601 and 2017YFC0907605).

References

  1. E. Kural-Seyahi, I. Fresko, N. Seyahi et al., “The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center,” Medicine, vol. 82, no. 1, pp. 60–76, 2003. View at: Publisher Site | Google Scholar
  2. U. Tursen, A. Gurler, and A. Boyvat, “Evaluation of clinical findings according to sex in 2313 Turkish patients with Behcet’s disease,” International Journal of Dermatology, vol. 42, no. 5, pp. 346–351, 2003. View at: Publisher Site | Google Scholar
  3. S. Farah, A. al-Shubaili, A. Montaser et al., “Behçet’s syndrome: a report of 41 patients with emphasis on neurological manifestations,” Journal of Neurology, Neurosurgery, & Psychiatry, vol. 64, no. 3, pp. 382–384, 1998. View at: Publisher Site | Google Scholar
  4. M. H. Houman, S. Bellakhal, T. B. Salem et al., “Characteristics of neurological manifestations of Behçet’s disease: a retrospective monocentric study in Tunisia,” Clinical Neurology and Neurosurgery, vol. 115, no. 10, pp. 2015–2018, 2013. View at: Publisher Site | Google Scholar
  5. D. L. Yoon, Y. J. Kim, B. S. Koo, Y. G. Kim, C. K. Lee, and B. Yoo, “Neuro-Behçet’s disease in South Korea: clinical characteristics and treatment response,” International Journal of Rheumatic Diseases, vol. 17, no. 4, pp. 453–458, 2014. View at: Publisher Site | Google Scholar
  6. A. Riera-Mestre, S. Martínez-Yelamos, A. Martínez-Yelamos, I. Ferrer, R. Pujol, and A. Vidaller, “Clinicopathologic features and outcomes of neuro-Behçet disease in Spain: a study of 20 patients,” European Journal of Internal Medicine, vol. 21, no. 6, pp. 536–541, 2010. View at: Publisher Site | Google Scholar
  7. A. Al-Araji and D. P. Kidd, “Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management,” The Lancet Neurology, vol. 8, no. 2, pp. 192–204, 2009. View at: Publisher Site | Google Scholar
  8. S. Daoudi, M. Lounis, and M. Ait-Kaci-Ahmed, “Parenchymal neuro-Behcet’s disease. Clinical and paraclinical characteristics, a report of 40 cases,” La Presse Médicale, vol. 43, no. 5, pp. e119–e125, 2014. View at: Publisher Site | Google Scholar
  9. B. Bitik, A. Tufan, K. Sahin et al., “The association between the parenchymal neurological involvement and posterior uveitis in Behçet’s syndrome,” Clinical and Experimental Rheumatology, vol. 34, Supplement 102, pp. 82–85, 2016. View at: Google Scholar
  10. E. Shugaiv, E. Tüzün, M. Mutlu, A. Kiyat-Atamer, M. Kurtuncu, and G. Akman-Demir, “Mycophenolate mofetil as a novel immunosuppressant in the treatment of neuro-Behçet’s disease with parenchymal involvement: presentation of four cases,” Clinical and Experimental Rheumatology, vol. 29, Supplement 67, pp. S64–S67, 2011. View at: Google Scholar
  11. G. Akman-Demir, P. Serdaroglu, and B. Tasci, “Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients,” Brain, vol. 122, Part 11, pp. 2171–2182, 1999. View at: Publisher Site | Google Scholar
  12. R. Talarico, A. d’Ascanio, M. Figus et al., “Behçet’s disease: features of neurological involvement in a dedicated centre in Italy,” Clinical and Experimental Rheumatology, vol. 30, Supplement 72, no. 3, pp. S69–S72, 2012. View at: Google Scholar
  13. International Study Group for Behcet's Disease, “Criteria for diagnosis of Behcet’s disease,” The Lancet, vol. 335, no. 8697, pp. 1078–1080, 1990. View at: Publisher Site | Google Scholar
  14. “The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria,” Journal of the European Academy of Dermatology and Venereology, vol. 28, no. 3, pp. 338–347, 2014. View at: Publisher Site | Google Scholar
  15. S. Kalra, A. Silman, G. Akman-Demir et al., “Diagnosis and management of Neuro-Behçet’s disease: international consensus recommendations,” Journal of Neurology, vol. 261, no. 9, pp. 1662–1676, 2014. View at: Publisher Site | Google Scholar
  16. J. L. Banks and C. A. Marotta, “Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis,” Stroke, vol. 38, no. 3, pp. 1091–1096, 2007. View at: Publisher Site | Google Scholar
  17. A. Al-Araji, K. Sharquie, and Z. Al-Rawi, “Prevalence and patterns of neurological involvement in Behcet’s disease: a prospective study from Iraq,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 74, no. 5, pp. 608–613, 2003. View at: Publisher Site | Google Scholar
  18. C. Lafitte, J. Servan, J. M. Bleibel, B. Wechsler, and J. Y. Delattre, “Meningomyelitis disclosing Behçet’s disease,” Revue Neurologique, vol. 152, no. 3, pp. 205–207, 1996. View at: Google Scholar
  19. M. K. Sharief, R. Hentges, and E. Thomas, “Significance of CSF immunoglobulins in monitoring neurologic disease activity in Behcet’s disease,” Neurology, vol. 41, no. 9, pp. 1398–1401, 1991. View at: Publisher Site | Google Scholar
  20. G. Akman-Demir, E. Tüzün, S. İçöz et al., “Interleukin-6 in neuro-Behçet’s disease: association with disease subsets and long-term outcome,” Cytokine, vol. 44, no. 3, pp. 373–376, 2008. View at: Publisher Site | Google Scholar
  21. O. Coban, S. Bahar, G. Akman-Demir et al., “Masked assessment of MRI findings: is it possible to differentiate neuro-Behçet’s disease from other central nervous system diseases? [corrected],” Neuroradiology, vol. 41, no. 4, pp. 255–260, 1999. View at: Google Scholar
  22. S. Hirohata, “Histopathology of central nervous system lesions in Behçet’s disease,” Journal of the Neurological Sciences, vol. 267, no. 1-2, pp. 41–47, 2008. View at: Publisher Site | Google Scholar
  23. S. Hirohata, H. Kikuchi, T. Sawada et al., “Clinical characteristics of neuro-Behcet’s disease in Japan: a multicenter retrospective analysis,” Modern Rheumatology, vol. 22, no. 3, pp. 405–413, 2012. View at: Publisher Site | Google Scholar
  24. Y. Ozguler, P. Leccese, R. Christensen et al., “Management of major organ involvement of Behçet’s syndrome: a systematic review for update of the EULAR recommendations,” Rheumatology, vol. 57, no. 12, pp. 2200–2212, 2018. View at: Publisher Site | Google Scholar
  25. G. Hatemi, R. Christensen, D. Bang et al., “2018 update of the EULAR recommendations for the management of Behçet’s syndrome,” Annals of the Rheumatic Diseases, vol. 77, no. 6, 2018. View at: Publisher Site | Google Scholar
  26. B. Zeydan, U. Uygunoglu, S. Saip et al., “Infliximab is a plausible alternative for neurologic complications of Behçet disease,” Neurology - Neuroimmunology Neuroinflammation, vol. 3, no. 5, p. e258, 2016. View at: Publisher Site | Google Scholar
  27. O. Addimanda, N. Pipitone, G. Pazzola, and C. Salvarani, “Tocilizumab for severe refractory neuro-Behçet: three cases IL-6 blockade in neuro-Behçet,” Seminars in Arthritis and Rheumatism, vol. 44, no. 4, pp. 472–475, 2015. View at: Publisher Site | Google Scholar
  28. G. Emmi, R. Talarico, G. Lopalco et al., “Efficacy and safety profile of anti-interleukin-1 treatment in Behçet’s disease: a multicenter retrospective study,” Clinical Rheumatology, vol. 35, no. 5, pp. 1281–1286, 2016. View at: Publisher Site | Google Scholar

Copyright © 2019 Dong Yan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

1015 Views | 416 Downloads | 1 Citation
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.