Clinical characterization and outcomes of 85 patients with neurosarcoidosis

1 Vol.:(0123456789) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports Clinical characterization and outcomes of 85 patients with neurosarcoidosis Manuel Ramos‑Casals1,2, Roberto Pérez‑Alvarez3, Belchin Kostov4,5, Ricardo Gómez‑de‑la‑Torre6, Carlos Feijoo‑Massó7, Joel Chara‑Cervantes8, Blanca Pinilla9, Andrés González‑García10, José‑Salvador Garcia‑Morillo11, Miguel López‑Dupla12, Begoña De‑Escalante13, Javier Rascón14, Patricia Perez‑Guerrero15, Mariona Bonet16, Gracia Cruz‑Caparrós17, Ana Alguacil18, José‑Luis Callejas19, Eva Calvo20, Cristina Soler21, Angel Robles22, Borja de Miguel‑Campo23, Pedro Oliva‑Nacarino24, Jorge Estela‑Herrero25, Lucio Pallarés14, Pilar Brito‑Zerón26*, Yolanda Blanco27 & the SarcoGEAS‑SEMI Registry* To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison OPEN 1Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain. 2Department of Medicine, University of Barcelona, Barcelona, Spain. 3Department of Internal Medicine, Hospital Alvaro Cunqueiro, Vigo, Spain. 4Primary Healthcare Transversal Research Group, IDIBAPS, Primary Care Center Les Corts, CAPSBE, Barcelona, Spain. 5Department of Statistics and Operational Research, Universitat Politècnica de Catalunya, Barcelona, Spain. 6Department of Internal Medicine, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain. 7Department of Internal Medicine, Hospital Parc Tauli, Sabadell, Spain. 8Department of Internal Medicine, Hospital Josep Trueta, Girona, Spain. 9Department of Internal Medicine, Hospital Gregorio Marañón, Madrid, Spain. 10Department of Internal Medicine, Hospital Ramon y Cajal, Madrid, Spain. 11Department of Internal Medicine, Hospital Virgen del Rocio, Seville, Spain. 12Department of Internal Medicine, Hospital Joan XXIII, Tarragona, Spain. 13Department of Internal Medicine, Hospital Clínico, Zaragoza, Spain. 14Department of Internal Medicine, Hospital Son Espases, Palma de Mallorca, Spain. 15Department of Internal Medicine, Hospital Puerta del Mar, Cádiz, Spain. 16Department of Internal Medicine, Althaia, Xarxa Assistencial de Manresa, Manresa, Spain. 17Department of Internal Medicine, Hospital de Poniente de El Ejido, Almería, Spain. 18Department of Internal Medicine, Hospital Virgen de la Salud, Toledo, Spain. 19Department of Internal Medicine, Hospital San Cecilio, Granada, Spain. 20Department of Internal Medicine, Hospital San Jorge, Huesca, Spain. 21Department of Internal Medicine, Hospital Santa Caterina, Girona, Spain. 22Department of Internal Medicine, Hospital La Paz, Madrid, Spain. 23Department of Internal Medicine, Hospital 12 de Octubre, Madrid, Spain. 24Department of Neurology. Hospital, Universitario Central de Asturias (HUCA), Oviedo, Spain. 25Department of Neurology, Hospital Parc Tauli, Sabadell, Spain. 26Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Hospital CIMA-Sanitas, Barcelona, Spain. 27Department of Neurology, Hospital Clínic, Barcelona, Spain. *A list of authors and their affiliations appears at the end of the paper. *email: [email protected] 2 Vol:.(1234567890) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis. Sarcoidosis is an immune-mediated granulomatous systemic disease1 that affects adults with a slight predominance in women at a mean age around 40 years2, with an estimated prevalence ranging between 1 and 40 cases per 100,000 individuals2,3. Sarcoidosis may mimic a wide variety of processes, and the diagnosis is established when specific clinical and imaging findings are supported by histologic evidence of non-caseating granulomas4. Spontaneous remission may occur in up to two thirds of patients, while the remaining cases may follow a chronic course5. The lungs and the thoracic lymph nodes are involved in nearly 90% of patients with sarcoidosis6. However, extrathoracic involvement is a key characteristic of the disease, and involvement of the nervous system (neurosarcoidosis) is one of the most characteristic systemic features involving around 3–9% of patients7,8. The clinical picture is heterogeneous since any part of the nervous system (brain, meninges, cranial nerves, spinal cord, peripheral nerves) can be affected9. Given the key role of histopathological examination for supporting the diagnosis of sarcoidosis, a major challenge regarding neurosarcoidosis is the difficulty of obtaining neural tissue, especially in those cases with involvement of the central nervous system. The diverse clinical presentation and the complex approach for obtaining neurological tissue make to consider neurosarcoidosis as one of the extrathoracic involvements more complex to diagnose and manage10. Despite numerous publications on neurosarcoidosis, there is no international consensus about their definition and classification. A variety of diagnostic criteria have been proposed in the last 20years with a wide methodological approach among them and therefore with significant limitations for being applied. A recent study from the Neurosarcoidosis Consortium Consensus Group has launched a consensus diagnostic set of criteria providing definitions for possible, probable and definite neurosarcoidosis10. In this study, we have analyzed the frequency and clinical phenotype of neurosarcoidosis in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe following these new diagnostic criteria. Methods Patients. The SARCOGEAS-Study Group was founded in 2015 with the aim of collecting a large series of patients with sarcoidosis from Spanish hospitals with substantial experience in the management of systemic autoimmune diseases6. Both incident and prevalent cases were included. By January 2020, the multicenter database included 1532 consecutive patients diagnosed with sarcoidosis in 40 centers according to the criteria proposed by the American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) 1999 statement on sarcoidosis11: (a) clinical or radiologic findings consistent with sarcoidosis, such as pulmonary disease, uveitis, mediastinal bilateral hilar lymphadenopathy (BHL), or erythema nodosum; (b) tissue biopsy with histologic evidence of non-caseating granulomas; (c) absence of other causes of granulomatous disease. Patients lacking the histopathological criteria (b) were included if they presented at least one of the following features: elevated serum angiotensin-converting enzyme, organ-specific abnormal uptake on gallium-67 citrate scintigraphy, elevated lymphocyte count or elevated CD4/CD8 ratio in bronchoalveolar lavage fluid, or active extrathoracic involvement classified as highly probable according to the WASOG extrathoracic classification12,13. Extrathoracic involvement at diagnosis was defined according to the 2014 WASOG organ assessment instrument, including only the clinical scenarios classified as highly probable or at least probable13. The study was conducted in accordance with the amended Declaration of Helsinki. The Ethics Committee of the coordinating center (Clinical Research Ethics Committee of the Hospital Clinic, Barcelona, Spain, code HCB2016/0181) approved the protocol, and written informed consent was obtained from patients with current follow-up. Variables. Patients included in the Registry as having neurosarcoidosis according to the 2014 WASOG definition were selected. These cases were re-evaluated according to the Proposed Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently reported by Stern etal.10. The mandatory inclusion criteria consisted of a clinical presentation and diagnostic evaluation suggesting neurosarcoidosis, as defined by the clinical manifestations and magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and/ or electromyogram/nerve conduction study (EMG/NCS) findings suggestive of granulomatous inflammation of the nervous system. Exclusion criteria included a rigorous exclusion of other causes of neurological disease. Pathologic confirmation of granulomatous disease was used to subclassify neurosarcoidosis into definite (noncaseating granulomas demonstrated in neurological tissue), probable (non-caseating granulomas demonstrated in extraneurological tissue) and possible (no histopathological confirmation of the disease)10 (Sup. Figure1). The following variables were retrospectively collected at the time of diagnosis of neurosarcoidosis, defined as the date of fulfilment of the Stern criteria: age, sex, signs and symptoms at neurological presentation, ACE serum levels, Scadding radiographic stages14, neurological diagnostic tests (MRI, CSF, EMG/NCS, PET), histopathological study, treatment and outcomes. The neurological diagnosis was achieved in each center after a multidisciplinary evaluation including neurologists, internists and radiologists, and was independently re-evaluated by MRC and YB, who applied the classification criteria and the subclassification into the 5 anatomical clusters proposed by Stern etal.10 (Sup. Table1), requiring to the participant centers additional information in case was necessary to confirm the fulfilment of the Stern criteria. 3 Vol.:(0123456789) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ Statistical analysis. Descriptive data are presented as mean and standard deviation (SD) for continuous variables and numbersand percentages(%) for categorical variables.Phenotyping comparisons were made considering the presence or absence of neurosarcoidosis, and among the two main subsets of neurosarcoidosis (peripheral and central nervous system involvement). The Chi-square test was used to studythe association between Scadding subsetswiththe main epidemiological, clinical, extrathoracic and therapeutic variables.Oneway ANOVA tests were used to compare continuous variables.All significance tests weretwo-tailed and values of p < 0.05 were considered significant.P-values were adjusted for multiplecomparisons using the false discovery rate (FDR) correction.All analyses were conducted using the R V.3.2.3 for Windows statistical software package(R: A Language and Environment for Statistical, R Core Team, R Foundation for Statistical Computing, Vienna, Austria, 2015, https:// www.R- proje ct. org/). Results Of the 1532 patients included in the cohort, 102 were reported as having neurosarcoidosis according to the WASOG criteria. Among them, 17 patients were excluded after applying the Stern criteria due to lack of enough information for applying the criteria (n = 11), lack of abnormal neurological diagnostic tests (n = 4) or other etiologies unrelated to sarcoidosis (n = 2). Therefore, the remaining 85 (5.5%) of patients fulfilled the Stern criteria for neurosarcoidosis and were specifically analysed. There were 49 (58%) women and 36 (42%) men, with a mean age at diagnosis of neurosarcoidosis of 47.6years (range 22–76); all patients except 8 were classified as White. Scadding radiologic stage consisted of stage 0 in 15 (18%) patients, stage I in 28 (33%), stage II in 31 (36%), stage III in 9 (11%) and stage IV in 2 (2%) patients. Histopathological demonstration of non-caseating granulomas was reported in 72 (85%) patients. In addition to the neurological involvement, 59 (69%) patients presented other extrathoracic manifestations and 21 (25%) presented only with thoracic manifestations; in the remaining 5 (6%) patients, the nervous system was the unique organ involved by sarcoidosis at the time of diagnosis (Table1). Anatomical involvements. The 85 patients with neurosarcoidosis developed 103 neurological conditions involving the brain (n = 39, 38%), cranial nerves (n = 37, 36%), the meninges (n = 3, 3%), the spinal cord (n = 10, 10%) and the peripheral nerves (n = 14, 14%). In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. Raised serum ECA levels were reported in 41/74 (55%) of cases. Forty-two patients had cerebrospinal fluid (CSF) analysis. Eight had completely normal CSF constituents. The most consistent abnormality was an elevated CSF protein (33/42 patients, 79%), followed by CSF pleocytosis (21/42 patients, 50%, with a range of 11–110 white cells, overwhelmingly monocytes). There were two cases of mild hypoglycorrhachia, in whom extensive microbiological studies were negative. Oligoclonal bands were studied in 8 patients (negative in 5, matched positive in 2 and positive with intrathecal synthesis alone in one). The CSF ACE level was measured in only one patient (normal levels). Table2 summarizes the demographics and therapeutic information of patients with neurosarcoidosis according to the different anatomical phenotypes. According to the classification proposed by Stern etal., 11 (13%) were classified as a definite neurosarcoidosis, 61 (72%) as a probable neurosarcoidosis and the remaining 13 (15%) as a possible neurosarcoidosis (Table1). Brain involvement. Brain involvement was reported in 39 patients (25 women, mean age at diagnosis of neurosarcoidosis of 46.1years). Neurological involvement preceded or was present at the time of diagnosis of sarcoidosis in 27 (69%) cases, and the nervous system was the only organ involved in 4 (10%). Clinical neurological presentation consisted of focal motor deficits (n = 14), headache (n = 12), clinical involvement of cranial nerves (n = 8), confusion/cognitive impairment (n = 7), seizures (n = 6), polyuria/polydipsia (n = 3), signs and symptoms of ICH (n = 2) and fever (n = 1); the neurological signs and symptoms often overlapped. Neurological imaging studies disclosed intraparenchymal brain lesions in 23 cases consisting of small subcortical or periventricular white matter lesions (n = 20) (Fig.1a) or 1–2 large isolated lesions (n = 3) (Fig.1b,c), leptomeningeal involvement in 18 (especially along the skull base, including the involvement of the pituitary tract in 6 patients) (Fig.2a), dural involvement in 5 (Fig.2b) and hydrocephalus in 2 cases; no patient showed stroke or intracerebral haemorrhage. Other diagnostic tests included abnormal PET uptake of the nervous system in 2/11 (18%) and abnormal CSF results in 22/25 (88%). There were 15 patients that presented with other concomitant anatomical neurological involvements (cranial nerves in 11, myelitis in 5, meningitis in one). According to the classification proposed by Stern etal., 8 (21%) were classified as a definite neurosarcoidosis, 25 (64%) as a probable neurosarcoidosis and the remaining 6 (15%) as a possible neurosarcoidosis. Frontline therapeutic approach included the use of corticosteroids in all patients except 2, including intravenous administration in 10 (methylprednisolone pulses in 8, dexamethasone in 2) and oral administration in the remaining 25 (with a dose higher than 30mg/day in 22 cases). Immunosuppressants were used in 13 patients (methotrexate in 7, azathioprine in 3, mycophenolate in 2, cyclophosphamide in 2) and biological therapies in 5 (infliximab in 4, adalimumab in 1, rituximab in 1); infliximab was stopped in 2 cases due to multiple episodes of infections (n = 1) and tuberculosis (n = 1). Data from therapeutic response was available in 36 cases showing a complete response in 21 (58%) cases, partial response in 13 (36%) and no response in 2 (6%). A relapse was reported in 6 patients, including 2 asymptomatic patients in neuroradiological studies disclosed disease progression. Cranial nerve involvement. Cranial nerve involvement was reported in 37 patients (25 women, mean age at diagnosis of neurosarcoidosis of 47.1years). Neurological involvement preceded or was present at the time of diagnosis of sarcoidosis in 26 (70%) cases, and the nervous system was the only organ involved in only 1 (3%) case. Clinical neurological presentation consisted of signs and symptoms suggestive of involvement of the VII (n = 24), II (n = 5), V (n = 2) and VI (n = 1) cranial nerves; the remaining 5 cases presented with multiple 4 Vol:.(1234567890) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ cranial nerve involvement (3 cases involving the ocular cranial nerves, one case involving the VII and XII and one involving the IX and X). Neurological imaging studies disclosed involvement of the optic nerves (Fig.3), together with other neurological involvements in 12 cases, mainly brain involvement in 11. Other diagnostic tests included abnormal PET uptake of the nervous system in 1/8 (12%) cases and abnormal CSF results in 10/15 (67%). According to the classification proposed by Stern etal., 2 (5%) were classified as a definite neurosarcoidosis, 27 (73%) as a probable neurosarcoidosis and the remaining 8 (22%) as a possible neurosarcoidosis. Frontline therapeutic approach included the use of corticosteroids in all patients except 3, including methylprednisolone pulses in 5, and oral administration in 29 (with a dose higher than 30mg/day in all cases). Immunosuppressants were used in 11 patients (methotrexate in 6, azathioprine in 2, mycophenolate in 2, cyclophosphamide in 2) and biological therapies in 2 (infliximab and rituximab, respectively). Data from therapeutic response was available in 35 cases in included a complete response in 23 (66%), partial improvement in 9 (26%) and no response in 3 (8%). Only 1 patient relapsed during the follow-up. Meningeal involvement. Three patients presented with lymphocytic meningitis (1 woman, mean age at diagnosis of neurosarcoidosis of 50years); in one case, neurological involvement preceded or was present at the time of Table 1. Epidemiological profile, clinical features and outcomes of 85 patients with neurosarcoidosis defined according to the Stern criteria. a Patients may have more than one involvement. N = 85 Frequency (%) Women 50 59 Mean age NS 47.6 White patients 78 92 Scadding radiological stages Stage 0 15 18 Stage I 28 33 Stage II 31 26 Stage III 9 11 Stage IV 2 2 Raised ECA 41/74 55 Bx-proven diagnosis 72 85 NRL presentation 59 69 Systemic phenotypes Isolated thoracic disease 21 25 Extrathoracic, non-NRL 59 69 Isolated NS 5 6 Neurosarcoidosis classification Definitive 11 13 Probable 61 72 Possible 13 15 Neurosarcoidosis involvementa Brain 39 38 Cranial nerves 37 36 Spinal cord 10 10 Meningitis 3 3 Peripheral nerves 14 14 Multiple neurological anatomical sites involved 16 19 Treatment Corticosteroids 76/83 92 Immunosuppresant agents 27/83 33 Biologics 3/83 4 Therapeutic response Complete response 47/78 60 Partial response 22/78 28 No response 9/78 12 Outcomes Relapse of NS 7/68 10 Death caused by NS 0 0 5 Vol.:(0123456789) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ diagnosis confirmation of the disease. All patients presented signs and symptoms of meningism (one together with paraparesia) and abnormal CSF studies, with normal neuroradiological studies. There were 2 patients that showed other concomitant anatomical neurological involvements. According to the classification proposed by Stern etal., all cases were classified as probable neurosarcoidosis. Frontline therapeutic approach included the use of corticosteroids with a dose higher than 30mg/day in all patients, and azathioprine was added in one case. A complete response was reported in 2 cases, while the remaining patient showed a partial response. One patient developed a haemorrhagic stroke during the follow-up. Spinal cord involvement. Spinal cord involvement was reported in 10 patients (5 women, mean age at diagnosis of neurosarcoidosis of 45.3years). In all cases, neurological involvement preceded or was present at the time of diagnosis confirmation of the disease, and the nervous system was the only organ involved in only 1 (10%) case. Clinical neurological presentation consisted of focal motor deficits (n = 9), headache (n = 3), meningism (n = 1) and cranial nerve involvement (n = 1). Neurological imaging studies disclosed intramedullary (Fig.4a) or extramedullary involvement (Fig.4b) (with dural enhancement on 4 cases) located in the cervical region (n = 3), the cervical and dorsal regions (n = 2), the dorsal region (n = 2) and the conus medullaris/cauda equina region (n = 2) (Fig.4c); enhancement extended for more than 3 segments in 5 patients. Abnormal CSF results were reported in 7/8 (88%). There were 5 patients that showed concomitant brain lesions. According to the classification proposed by Stern etal., 8 (80%) were classified as a probable neurosarcoidosis and the remaining 2 (20%) as a possible neurosarcoidosis. Frontline therapeutic approach included the use of corticosteroids with a dose higher than 30mg/day in all patients (including methylprednisolone pulses in one case). Immunosuppressants were used in 5 patients (methotrexate in 3, mycophenolate in 2, cyclophosphamide in 1) and biological therapies in 1 (infliximab). Data from therapeutic response showed a complete response in 3 (30%), partial improvement in 6 (60%) and no response in 1 (10%, no response to MMF, IFX started but stopped for infections). One patient relapsed at 6-months of follow-up during corticosteroid tapering. Neuropathy. Peripheral nerve involvement was reported in 14 patients (5 women, mean age at diagnosis of neurosarcoidosis of 50.4years). In 11 cases, neurological involvement preceded or was present at the time of diagnosis confirmation of the disease. Clinical neurological presentation consisted of signs and symptoms suggestive of sensory neuropathy in 12 cases and radicular paresthesia/paraparesis in the remaining 2. Electromyogram/nerve conduction studies disclosed axonal polyneuropathy (n = 7), pure sensitive neuropathy/small fiber neuropathy (n = 4), polyradiculopathy (n = 2) and inconclusive, non-classified polyneuropathy (n = 1). Neurological imaging studies were normal in 7/7. Other diagnostic tests included abnormal CSF results in 6/7 (86%). No patients showed concomitant involvement of the central nervous system. According to the classification proposed by Stern etal., 2 (14%) were classified as a definite neurosarcoidosis, 11 (79%) as a probable neurosarcoidosis and the remaining one (7%) as a possible neurosarcoidosis. Frontline therapeutic approach included the use of corticosteroids in 10 (71%) cases, including methylprednisolone pulses in 2, and oral administration in 8 (with a dose higher than 30mg/day in 6 cases). Immunosuppressants were used in 2 patients (methotrexate) Table 2. Demographics and therapeutic information of patients with neurosarcoidosis according to the different anatomical phenotypes. Brain involvement (n = 39) Cranial nerve involvement (n = 37) Meningeal involvement (n = 3) Spinal cord involvement (n = 10) Neuropathy (n = 14) Sex (women) 25 (64%) 25 (68%) 1 (33%) 5 (50%) 5 (36%) Mean age at diagnosis (mean) 46.1years 47.1years 50.0years 45.3years 50.4years Neurological presentation Preceded/coincident with sarcoidosis diagnosis 27 (69%) 26 (70%) 1 (33%) 10 (100%) 11 (79%) Nervous system as the only organ involved 4 (10%) 1 (3%) 0 (0%) 1 (10%) 0 (0%) Neurosarcoidosis classification (Stern etal.) Definitive 8 (21%) 2 (5%) 0 (0%) 0 (0%) 2 (14%) Probable 25 (64%) 27 (73%) 3 (100%) 8 (80%) 11 (79%)) Possible 6 (15%) 8 (22%) 0 (0%) 2 (20%) 1 (7%) Multiple neurological anatomical sites involved 15 (38%) 12 (32%) 2 (67%) 5 (50%) 0 (0%) Treatment Corticosteroids 37 (95%) 34 (92%) 3 (100%) 10 (100%) 10 (71%) Immunosuppresant/biologic agents 14 (36%) 11 (30%) 1 (33%) 5 (50%) 2 (14%) Therapeutic response Complete response 22/36 (61%) 23/35 (66%) 2 (67%) 3 (30%) 5/11 (45%) Partial response/no response 14/36 (39%) 12/35 (34%) 1 (33%) 7 (70%) 6/11 (55%) Relapse in complete responders 6/22 (27%) 1/23 (4%) 0 (0%) 1/3 (33%) 0/5 (0%) 6 Vol:.(1234567890) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ Figure1. Intraparenchymal lesions. Pontine right lateral lesion that enhances with gadolinium: (a) Flair sequence and (b) T1 sequence with gadolinium; (c) Subcortical white matter lesions, Flair sequence. 7 Vol.:(0123456789) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ and IVIG in 1. Data from therapeutic response was available in 11 cases and included a complete response in 5 (45.5%), partial improvement in 1 (9%) and no response in 5 (45.5%). Comparison studies. Differences according to anatomical involvement. No significant differences were found between patients with CNS involvement and those with PNS involvement except for a trend for a higher frequency of women in patients with CNS involvement and a higher frequency of renal involvement in those with PNS involvement (14% vs 0%, p = 0.025) (Table3). In patients with CNS involvement, no significant differences were found between those with brain involvement and those with CNS involvement out of the brain except for a higher frequency of multiple anatomical involvements in patients with brain involvement (38% vs 3%, p < 0.001) (Sup. Table2). Patients presenting with a unique CNS neurological involvement showed a higher frequency of raised ECA levels (62% vs 29%, p = 0.036) and a lower frequency of salivary gland involvement (10% vs 31%, p = 0.044) in comparison with those with multiple CNS sites involved (Sup. Table3). Comparison with patients without neurosarcoidosis. Patients with CNS neurosarcoidosis presented a higher frequency of radiological Scadding Stage 0 (18% vs 7%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements, and a higher frequency of use of corticosteroids (96% vs 47%, q < 0.001) and immunosuppressive/biological agents (35% vs 8%, q < 0.001) in comparison with patients without neurosarcoidosis, while those with PNS neurosarcoidosis showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) and a trend for a higher frequency of spleen involvement (21% vs 7%, p = 0.08) that were not statistically significant in the corrected statistical analysis (Table3). Figure2. Leptomeningeal and dural involvement. (a) Diffuse leptomeningeal involvement and involvement of the pituitary tract; (b) Dural involvement. 8 Vol:.(1234567890) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ Discussion Neurosarcoidosis is a potentially life-threatening presentation of sarcoidosis that has been reported in 3–9% of patients with sarcoidosis7,8,15–18. There are few large studies focusing on the characterization of this extrathoracic presentation of sarcoidosis, with only 7 series including more than 30 cases that have been published in the last 20years, mainly from the US19–23 and Northern Europe9,24 (Sup. Table4). In this study, we have characterized the largest series of patients with neurosarcoidosis from Southern Europe, and the second one reported worldwide, using for the first time the new diagnostic criteria proposed by Stern etal.10. Neurosarcoidosis was identified in 5.5% of our patients with sarcoidosis, a similar figure than that reported in previous cohorts of patients7,8,15–18. According to previous studies (Sup. Table4), patients with neurosarcoidosis are women in 44–77% of cases, with a frequency of non-White people ranging between 40 and 96%, and a mean age at diagnosis of the neurological disease ranging from 40 to 48years; neurosarcoidosis is present at the time of diagnosis of sarcoidosis in 60–72% of cases, and is the single organ involved in 3–20% of reported cases. The epidemiological profile in our series was quite similar (59% women, mean age at diagnosis around 48years), and also the timing of presentation (neurosarcoidosis was present at the time of diagnosis in 59% of cases being the single organ involved in 6%). We report one of the oldest mean age at diagnosis of neurosarcoidosis among the large reported series, a fact that could be linked with having the reported series with the highest frequency of White people (92% of our cases, in comparison with only 4–60% of patients included in previous studies) (Sup. Table4), since sarcoidosis is diagnosed at older ages in White patients in comparison with other ethnicities2. Among patients with CNS involvement, we found a clear predominance of brain (55%) and cranial nerve (52%) involvements, and a low frequency of spinal cord (14%) and meningeal (4%) involvements. The main studies show that brain (33–52%) and cranial nerve (31–76%) involvements also are the predominant presentation of neurosarcoidosis18,19,22,24–30, as has also been confirmed in a recent systematic review analysing 652 patients with neurosarcoidosis (parenchymal brain lesions were reported in 51% of cases and cranial neuropathies in 55%)31. We found that intraparenchymal lesions and leptomeningeal involvement were the key features of sarcoidosis involving the brain, as has reported by previous studies9,22; we also found involvement of the pituitary tract, a very specific site involved by neurosarcoidosis32, in 9% of patients, a frequency that is into the range of that previously reported (2–25%)19,21–24. Pathological studies in patients with sarcoidosis involving the brain showed microvascular changes (involving small arteries, arterioles and small veins) and granulomatous inflammation often following a perivascular distribution26, as we could see in 3 of our patients in whom brain biopsy was carried out. Brain neurosarcoidosis is characterized by a mixed cellular infiltration composed by histiocytes, macrophages, both CD4 and CD8 T lymphocytes and B lymphocytes. In our patients with brain involvement, we reported a complete/partial response in more than 90% of cases; in previous studies19,21–24, we cannot found specific data about the therapeutic response in patients with sarcoidosis involving the brain, since the main series do not separate the therapy and outcome of these patients from other patients with neurosarcoidosis. We found cranial nerve involvement in half of our patients with neurosarcoidosis; involvement of the facial nerve represented 65% of all cranial neuropathies we identified. In the systematic review by Fritz etal.31, the facial nerve was also the most frequent cranial nerve involved (40%), followed by the optic, trigeminal and Figure3. Involvement of optic chiasm and hypophysis; (a) T1 sequence; (b) T1 sequence after gadolinium. 9 Vol.:(0123456789) Scientific Reports | (2021) 11:13735 | https://doi.org/10.1038/s41598-021-92967-6 www.nature.com/scientificreports/ Figure4. Medullary involvement: (a) Intramedullary involvement; (b) Extramedullary involvement; (c) Gadolinium enhancement at cauda equina (T1 sequence and T1 sequence after gadolinium).