Neurosarcoidosis Patients Research Articles

Diagnostic value of soluble Interleukin-2 receptor in patients suffering neurosarcoidosis: A systematic review.

Neurosarcoidosis is an inflammatory granulomatous disease. Up to 25% of occult sarcoidosis affecting the nervous system are only detected by autopsy. In addition, in recent years the suspicion arose that the soluble Interleukin-2 Receptor (sIL-2R) might be useful in differentiating between neurosarcoidosis and neurosarcoidosis-like diseases such as neurotuberculosis, multiple sclerosis, or cerebral lymphoma. Therefore, we aimed to systematically review randomized controlled trials (RCT), observational studies, and case-control studies evaluating sIL-2R levels in neurosarcoidosis patients. For this systematic review, a comprehensive literature search of electronic databases including EMBASE, The Web Of Science, The Cochrane Library, MEDLINE, and Google Scholar was conducted. The search was limited to the English language and publication date up to January 08th, 2024. As part of the search strategy conducted, 6 articles met the inclusion criteria. Two independent reviewers extracted the relevant data from each article. In addition, 2 independent reviewers assessed the quality of each study using the Newcastle-Ottawa Scale (NOS). We included 6 studies comprising 98 patients suffering from neurosarcoidosis, 525 non-sarcoidosis patients, and 118 healthy controls. Included studies were published between 2010 and 2023. Cerebrospinal fluid (CSF) sIL-2R levels differed significantly between neurosarcoidosis patients and multiple sclerosis, vasculitis, and healthy controls whereas serum sIL-2R levels did not reveal sufficient discriminative power. sIL-2R index was able to discriminate neurosarcoidosis from neurotuberculosis, bacterial/viral meningitis, and healthy controls. In this systematic review, we found indications that sIL-2R may be a useful biomarker for the diagnosis of neurosarcoidosis. To determine an additional diagnostic value of sIL-2R, large prospective studies are needed that not only examine absolute sIL-2R levels in serum or CSF but also the dynamic changes as well as the implications of renal function on sIL-2R levels.

Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights.

To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication. In this case-control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011-02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls. A total of 32 NS patients (59% women; median age, 59 years [19-81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity. NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024.

Infliximab in neurosarcoidosis: a systematic review and meta-analysis.

To evaluate the clinical outcomes and relapse rates in neurosarcoidosis patients administered infliximab. A systematic review was conducted using the MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases. The search included studies from their inception to March 2023. We included case-series studies with at least 10 neurosarcoidosis patients undergoing any treatment type. Studies were also required to report at least one of the following outcomes: response rate, overall survival rate, or relapse rate. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model facilitated the analysis of proportional treatment outcomes. Study quality was evaluated using the modified Newcastle-Ottawa quality assessment scale, while a funnel plot helped detect any publication bias. Seven studies comprising 237 patients with neurosarcoidosis were included in the analysis. Of these patients, 184 (77.6%) received treatment with infliximab. The pooled proportion of patients showing clinical improvement after infliximab treatment was 0.74 (95% CI 0.64-0.84, I2 = 49.73%). Relapse rates, derived from four studies, stood at 0.38 (95% CI 0.22-0.55, I2 = 56.92%). Most studies reported successful tapering or cessation of corticosteroid dosage in patients receiving infliximab. Adverse effects were reported in 52 (29.4%) patients, of which 39 out of 54 events (72.2%) were linked to infections. Infliximab demonstrated potential improvement in clinical outcomes for patients with refractory neurosarcoidosis and showed potential for reducing the dosage of concurrent corticosteroids. However, a degree of relapse was observed, with infections being the primary concern for adverse events.

Cerebral lesions sites in neurosarcoidosis: a lesion mapping study.

Sarcoidosis is a granulomatous disease of unknown etiology affecting the central nervous system in up to 15% of the patients. Diagnosis of neurosarcoidosis is very challenging due to the heterogeneity of its clinical manifestation. This study intended to evaluate the distribution of cerebral lesion sites and the potential presence of specific lesion clusters in neurosarcoidosis patients using voxel-based lesion symptom mapping (VLSM). Patients with neurosarcoidosis were retrospectively identified and included between 2011 and 2022. Cerebral lesion sites were correlated voxel-wise with presence and absence of neurosarcoidosis using non-parametric permutation test. Multiple sclerosis patients served as controls for the VLSM-analysis. Thirty-four patients (mean age 52 ± 15years) of whom 13 were diagnosed with possible, 19 with probable and 2 with confirmed neurosarcoidosis were identified. Lesion overlap of neurosarcoidosis patients demonstrated a distribution of white matter lesions in all brain areas, with a periventricular predilection similar to multiple sclerosis. In contrast to multiple sclerosis controls, no propensity for lesions in proximity of the corpus callosum was observed. Neurosarcoidosis lesions appeared smaller and lesion volume was lower in the neurosarcoidosis cohort. The VLSM analysis showed minor associations between neurosarcoidosis and damaged voxels in the bilateral frontobasal cortex. The VLSM analysis yielded significant associations in the bilateral frontal cortex, suggesting that leptomeningeal inflammatory disease with following cortical involvement is a quite specific feature in neurosarcoidosis. Lesion load was lower in neurosarcoidosis than in multiple sclerosis. However, no specific pattern of subcortical white matter lesions in neurosarcoidosis was revealed.

Krebs von den Lungen-6 (KL-6) in cerebrospinal fluid from neurosarcoidosis patients.

Krebs von den Lungen-6 (KL-6) is a high molecular weight (MW) glycoprotein mainly secreted by type II pneumocytes because of lung damage or during regeneration. Neurosarcoidosis (NS), where sarcoid granulomas involve the nervous system, occurs in 5-20% of patients with sarcoidosis. No data is currently available on KL-6 in serum or CSF of NS patients. The present study compared KL-6 concentrations in serum and CSF of NS patients versus others with neurodegenerative (ND) or chronic inflammatory demyelinating (DM) diseases. Nine NS patients (mean age 46.2 years, range 16-61 years, M/F 5/4), nine patients with a chronic neurodegenerative disease (mean age 53.1 years, range 37-65 years, M/F 5/4) and nine patients with a chronic demyelinating disease (mean age 46.3 years, range 18-65 years, M/F 5/4) were retrospectively enrolled. Measurable CSF concentrations of KL-6 were detected in 7/9 NS patients but in no ND or DM patients. No significant differences in CSF concentrations of ACE were observed between the three groups (p=0.0819). In NS patients, CSF concentrations of KL-6 were directly correlated with CSF albumin index (r=0.98; p<0.0001), albumin (r=0.979, p=0.0001), IgG (r=0.928, p=0.0009) and total protein concentrations (r=0.945, p=0.0004). KL-6 is a high MW protein, under physiological conditions it is unlikely to cross the blood-brain barrier. We found KL-6 in CSF from NS and not from ND and DM patients. The finding sustains the specificity of changes in KL-6 in this granulomatous disease, suggesting it as a candidate biomarker for recognition of NS.

Cardiac Involvement In Neurosarcoidosis: A Single Center Investigation (P9-5.004)

<h3>Objective:</h3> Describe the frequency of coexistent cardiac disease in a cohort of Neurosarcoidosis (NS) patients. <h3>Background:</h3> Sarcoidosis is a multisystem granulomatous inflammatory disease. We report the incidence of cardiac sarcoidosis in our NS cohort and examined the frequency of other cardiac diseases in the cohort. <h3>Design/Methods:</h3> Of 64 probable/definite NS patients in the University of Utah cohort, 52 patients had at least one electrocardiogram (ECG) and were included in analysis. <h3>Results:</h3> Of 52 NS patients with ECG, 65% were female with average age 60.9 (38–84). 58% had a BMI&gt;30. Symptoms suggestive of cardiac dysfunction included: leg swelling (50%), palpitations (46%), chest pain (44%) and dyspnea (44%). Ten patients (19%) had at least one myocardial infarction confirmed by cardiology. ECG abnormalities included non-specific T wave change (40%), right bundle branch block (RBBB) (19%), AV block (16%), and QT prolongation (12%). 10 patients had sinus tachycardia, 5 had sinus bradycardia, and 1 each had ventricular tachycardia (VT) and non-sustained VT. Six patients required implantable cardioverter-defibrillator placement and one required a pacemaker. Cardiac MRI on 17 patients (33%) revealed 3 (17%) with diffuse myocardial enhancement possibly suggesting cardiac sarcoidosis (CS). All had leg swelling, plus one each with orthopnea, syncope, or dyspnea. Myocardial PET scan was performed on 9 NS patients, confirming 3 known CS, and revealing one newly diagnosed CS, who had leg swelling and dyspnea. 2 additional patients had ICD placement after detection of high-grade AV block and persistent atrial fibrillation, respectively, but no evidence of CS on cardiac MRI. Of 6 confirmed CS patients, 3 patients manifested initially as NS. <h3>Conclusions:</h3> Of 52 NS patients, 12% had cardiologist-confirmed CS. Non-sarcoid cardiac illness was also common, emphasizing the need for comprehensive cardiac evaluation in NS. Research is needed to determine if sarcoid-related morbidity may contribute to increased all-cause cardiac disease. <b>Disclosure:</b> Dr. Noroozi Gilandehi has nothing to disclose. Mr. Wong has nothing to disclose. Dr. Wright has nothing to disclose. Dr. Lord has nothing to disclose. Mr. Stehlik has nothing to disclose. Dr. Kemeyou has nothing to disclose. Dr. Clardy has received personal compensation for serving as an employee of Veterans Health Administration (VHA). Dr. Clardy has received personal compensation for serving as an employee of University of Utah Health. Dr. Clardy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology/AAN Publications. The institution of Dr. Clardy has received research support from Sumaira Foundation for NMO. The institution of Dr. Clardy has received research support from Western Institute for Veteran Research. The institution of Dr. Clardy has received research support from NIH/NINDS. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a AAN Summer Meeting CoDirector Travel and Lodging with AAN. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Grand Rounds Travel and Lodging with U of Iowa. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Barrow Neurological Institute. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Beaumont Health.

A Familial Analysis of Neurosarcoidosis Utilizing the Utah Population Database (P9-5.008)

<h3>Objective:</h3> To investigate for evidence of familial clustering within a large cohort of patients with Neurosarcoidosis utilizing the Utah Population Database. <h3>Background:</h3> Sarcoidosis is a multisystemic inflammatory disease that can affect the cardiac, integumentary, hepatic, renal, ocular, and neurologic systems. Neurologic manifestations include cranial neuropathies, meningitis, peripheral neuropathy, myelopathy, intraparenchymal mass lesions. Current evidence suggests familial clustering of sarcoidosis in Sweden as well as within the US Black population. Genes of interest include HLA-DP subregions, Annexin A11, Butyrophilinlike 2 gene, and Toll-like receptors. We investigated for evidence of shared genetics among our Intermountain West cohort of neurosarcoidosis patients. <h3>Design/Methods:</h3> We performed a retrospective review of all definite and probable neurosarcoidosis patients diagnosed and managed at our institution. Using the Utah Population Database (UPDB), a population-based genealogic resource containing medical and demographic information of over 11 million individuals, we identified high-risk pedigrees with excess familial aggregation of neurosarcoidosis using the Familial Standardized Incidence Ratio (FSIR). Unaffected subjects were identified and matched 10:1 to neurosarcoidosis patients by age, birth year, and pedigree structure in the UPDB. Familial risk analyses were performed to estimate the heritability of neurosarcoidosis FDRs, SDRs, and TDRs separately using multivariate logistic regression adjusting for sex, birth year, race, and ethnicity. <h3>Results:</h3> Out of the 54 patients in the cohort, the median age of patients was 63 years (SD 12 years), 36(66%) were female and 46 (85%) self-identified as Caucasian. A total of 12 (22%) had definite neurosarcoidosis and 42 (78%) had probable neurosarcoidosis. The initial symptom of sarcoidosis was neurologic in 34 (63%) of the patients. We studied the inter-relatedness of the patients with neurosarcoidosis. <h3>Conclusions:</h3> Neurosarcoidosis is a rare disease and thought to be a manifestation of a multisystem disease in which familial clustering and genetic analysis suggests that inherited factors play a role in the pathogenesis which requires further investigation. <b>Disclosure:</b> Dr. Crane has nothing to disclose. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon. Mr. Yu has nothing to disclose. Ms. Date has stock in Astrazeneca. Mr. Madsen has nothing to disclose. Ms. Fraser has nothing to disclose. Mr. Wong has nothing to disclose. Dr. Lord has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Clardy has received personal compensation for serving as an employee of Veterans Health Administration (VHA). Dr. Clardy has received personal compensation for serving as an employee of University of Utah Health. Dr. Clardy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology/AAN Publications. The institution of Dr. Clardy has received research support from Sumaira Foundation for NMO. The institution of Dr. Clardy has received research support from Western Institute for Veteran Research. The institution of Dr. Clardy has received research support from NIH/NINDS. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a AAN Summer Meeting CoDirector Travel and Lodging with AAN. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Grand Rounds Travel and Lodging with U of Iowa. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Barrow Neurological Institute. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Beaumont Health.

COVID-19 Outcomes in Neurosarcoidosis (P9-5.012)

<h3>Objective:</h3> To investigate outcomes of coronavirus disease 2019 (COVID-19) in neurosarcoidosis (NS). <h3>Background:</h3> A prior study investigating COVID-19 outcomes in systemic sarcoidosis has identified patients with neurologic involvement to be at increased risk for COVID-19 complications. Questions remain regarding what features of neurosarcoidosis predispose to a more severe COVID-19 course. <h3>Design/Methods:</h3> Patients diagnosed with neurosarcoidosis were included if the electronic medical record indicated the patient had been infected with COVID-19. <h3>Results:</h3> Twenty-one patients with NS were included with a median age of 57 years (range 22–75) and median illness duration of 96 months (range 2–348) at the time of the COVID-19 infection. Eight (38.1%) had active-uncontrolled NS disease, five (23.8%) had active-controlled disease, and eight (38.1%) had inactive disease. 15/21 (71.4%) were on immunosuppressants, most commonly steroids (12, 57.1%), infliximab (9, 42.9%), and methotrexate (8, 38.1%). 10/21 (47.6%) had documented vaccination records against COVID-19 prior to the infection, while the remaining were un- or inadequately vaccinated. No adverse reactions to vaccinations were reported. Only one patient was asymptomatic of COVID-19. 7/20 (35.0%) patients (all immunosuppressed and 5 vaccinated) required hospital admission for a median of 7 days, including one unvaccinated patient (1/19, 5.3%) in a ventilated ICU setting. 8 patients (8/21, 38.1%) received anti-COVID treatments (remdesivir, monoclonal antibodies, or nirmatrelvir/ritonavir), all but one of which were immunosuppressed and five of which were vaccinated. Adjustments to immunosuppressants were made in 4 patients (4/21, 19.0%) during the active infection. 18/21 (85.7%) recovered completely from infection. One (1/21, 4.7%) patient died from COVID-19. 2/17 patients (11%) with follow-up data experienced clinical symptoms suggestive of NS relapse or progression within 90 days of infection. <h3>Conclusions:</h3> Most NS patients experienced symptomatic COVID-19 infection, including a higher rate of hospitalization than previously reported in the general population. Most patients experiencing severe disease were immunosuppressed and vaccinated. <b>Disclosure:</b> Dr. El Sammak has nothing to disclose. Dr. Bou has nothing to disclose. Dr. Hutto has nothing to disclose.

Neurosarcoidosis: Phenotypes, Approach to Diagnosis and Treatment.

The aim of this review is to provide an update of clinical presentation, diagnosis, differential diagnoses, and treatment according to recent evidence. Neurosarcoidosis remains a diagnosis of exclusion, with infectious and malignant etiologies recognized as important mimickers. Corticosteroids remain as first-line therapy. In recent years, however, studies have demonstrated the effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in the treatment of neurosarcoidosis, leading to improved outcomes. Neurosarcoidosis is a granulomatous disease with protean manifestations that may affect any part of the central and peripheral nervous system. It has many mimickers, and potentially devastating complications necessitating long-term follow-up. Early initiation of treatment, particularly with anti-TNF therapy, may lead to better outcomes and fewer relapses. There is an unmet need for randomized controlled trials that provide robust data to guide therapy and the long-term management of neurosarcoidosis patients.

Inflammatory profiles in plasma and cerebrospinal fluid of patients with neurosarcoidosis

MethodsCerebrospinal fluid (CSF) and plasma levels of 38 biomarkers from 20 neurosarcoidosis (NS) patients were compared to healthy controls (HC). ResultsIn CSF, 25 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, TNFβ, IL-2, IL-6, IL-10, IL-12B, IL-15, IL-16, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26, CXCL8, CXCL10, TNFR2, VEGF-A, PIGF, SAA, VCAM1, and ICAM1.In plasma, 12 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, CCL2, CCL3, CCL4, CCL17, CXCL10, VEGFR1, PIGF, SAA, VCAM1, and ICAM1. ConclusionNS patients have profoundly elevated cytokines, chemokines, vascular angiogenesis, and vascular injury biomarkers in CSF and plasma.

Clinical characteristics and outcome of neurosarcoidosis-associated myelitis: A retrospective cohort study and review of the literature.

Background and purposeNeurosarcoidosis can affect all parts of the nervous system of which myelitis is relatively frequent. The aim of this study was to describe clinical characteristics, treatment and prognosis of patients with myelitis attributable to neurosarcoidosis.MethodsWe performed a retrospective cohort study and a systematic review and meta‐analysis of neurosarcoidosis‐associated myelitis.ResultsMyelitis was identified in 41 of 153 (27%) neurosarcoidosis patients seen at our clinic from 2015 to 2020. Classification of neurosarcoidosis was definite in three (7%), probable in 29 (71%) and possible in nine patients (22%). The median (interquartile range) age at onset was 49 (41–53) years and 20 of the patients were female (49%). The presenting symptoms included muscle weakness in 31 of 41 patients (78%), sensory loss in 35 (88%) and micturition abnormalities in 30 (75%). Spinal magnetic resonance imaging showed longitudinally extensive myelitis in 27 of 36 patients (75%) and cerebrospinal fluid examination showed an elevated leukocyte count in 21 patients (81%). Initial treatment consisted of glucocorticoids in 38 of 41 patients (93%), with additional methotrexate or azathioprine in 21 of 41 patients (51%) and infliximab in 10 of 41 patients (24%). Treatment led to remission, improvement or stabilization of disease in 37 of 39 patients (95%). Despite treatment, 18 of 30 patients (60%) could not walk independently at the end of follow‐up (median 36 months). A review of the literature published between 2000 and 2020 identified 215 patients with comparable clinical characteristics and results of ancillary investigations.ConclusionSarcoidosis‐associated myelitis is observed in 27% of neurosarcoidosis patients. Although treatment often led to a decrease in disease activity, residual neurological deficits leading to loss of ambulation occurred frequently.

Clinical characteristics and outcome of hydrocephalus in neurosarcoidosis: a retrospective cohort study and review of the literature

Hydrocephalus is reported in approximately one-tenth of neurosarcoidosis patients. However, data on clinical characteristics and outcome are lacking. In this retrospective study, we present 11 patients with neurosarcoidosis and hydrocephalus on neuroimaging. Median age was 52 years and seven were female (64%). Presenting symptoms consisted of headache in 8 out of 11 (73%), vertigo in 5 (46%), gait abnormalities in 4 (36%), diplopia in 2 (18%) and decreased visual acuity in 1 (9%). Cranial imaging showed obstructive hydrocephalus in 10 (91%) and non-obstructive hydrocephalus in 1 (9%) out of 11, obstruction occurred at the level of the fourth ventricle in 6 out of 10 (60%). Treatment consisted of glucocorticoids in all the patients with additional methotrexate or azathioprine in 6 (55%) and infliximab in 1 (9%) patient. Neurosurgical intervention was performed in 10 out of 11 (91%) patients. Treatment led to remission, improvement or stabilization of disease in 9 out of 10 (90%) of patients. One patient died due to cerebral herniation despite neurosurgical decompression and CSF shunting. Median modified Rankin scale score at last follow-up was 2 (range 0–6). A systematic review and meta-analysis of studies on hydrocephalus due to neurosarcoidosis identified 36 patients that compared to our patients had a lower median age at onset and a higher mortality. Acute obstructive hydrocephalus due to neurosarcoidosis is a potentially fatal medical emergency requiring neurosurgical intervention and initiation of immunosuppressive therapy. If patients survive the initial phase, the outcome is generally favorable.

Neurosarcoidosis mimicry of MS: Clues from cases with CNS tissue diagnosis

The clinical picture of neurosarcoidosis (NS) shares many aspects with multiple sclerosis (MS). I examine whether or not clinical measures can reliably distinguish NS mimicking MS from NS coexisting with MS, and the informative role biopsy and autopsy evidence may play in understanding these two disorders. Uniquely challenging, I explore the rare patients presenting with the differential of MS or acute disseminated encephalomyelitis (ADEM) versus NS, including MS or ADEM as an associated illness in patients with systemic sarcoidosis. In most but not all NS patients, red flags against a diagnosis of MS are strong enough to rule out this more common disorder. Biopsy and autopsy findings indicate a tendency of NS granulomatous changes in the CNS to involve the same deep white matter perivascular spaces as expected to occur in MS, and hence correlate with a tendency of NS involving white matter to produce classic MRI findings of MS. The spectrum of NS includes some cases limited to a single anatomical site, including sites classically involved in demyelinating CIS (optic nerve, brainstem, and transverse myelitis). Asymptomatic “non-specific” periventricular MRI changes are described in many studies as “MS-like”. No biopsied or autopsied cases have yet proven associated classic pathological changes of MS in patients with NS.

MRI findings in Neurosarcoidosis Patients with Headache as a Primary Presenting Symptom (5025)

MRI findings in Neurosarcoidosis Patients with Headache as a Primary Presenting Symptom (5025)

Elevated Neurofilament Light Chain in Cerebrospinal Fluid and Plasma Reflect Inflammatory MRI Activity in Neurosarcoidosis.

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.

Effects of immunotherapies and clinical outcomes in neurosarcoidosis: a retrospective cohort study.

Neurosarcoidosis is associated with a significant degree of morbidity and mortality and its treatments are varied and complex. There is a paucity of information in current literature on patterns of treatment and long term outcomes. This study aimed to evaluate the clinical outcomes and responses to immunosuppressive therapy in a large cohort of neurosarcoidosis patients . We enrolled 80 patients with a diagnosis of neurosarcoidosis. Prescription patterns and clinical outcomes before and after treatment and differences between the treatment groups were compared using Kruskal-Wallis and Mann-Witney U tests. Patients with cranial mononeuropathy other than optic neuropathy were more likely to be treated with steroids alone whereas patients with other presentations were likely to require second and third level treatments. These included azathioprine, methotrexate, mycophenolate, infliximab, and cyclophosphamide often used in combination. Prednisolone alone at onset failed in 67% of patients but appeared most effective in those with isolated facial nerve palsy. Patients treated with prednisolone plus a standard immunosuppression first line generally did well except for those with brain parenchymal disease and /or hydrocephalus who responded better to the addition of infliximab, or cyclophosphamide. Triple therapy with prednisolone + azathioprine + infliximab was associated with significantly greater improvement on the Modified Rankin Scale than prednisolone alone whether used first line (p = 0.001 corrected) or subsequently (p = 0.021 corrected). Overall favourable outcomes in the form of improvement of MRS were reported in 87%, CONCLUSIONS: Our results provides evidence that early immunosuppressive treatments, with azathioprine, methotrexate and infliximab could effectively improve clinical outcomes in many patients with neurosarcoidosis.

Retrospective, dual-centre review of imaging findings in neurosarcoidosis at presentation: prevalence and imaging sub-types

To assess the prevalence of various imaging manifestations in neurosarcoidosis (NS) patients at presentation and to explore if specific imaging findings may cluster in different sub-groups. A retrospective, dual-institution, systematic imaging review was undertaken of the magnetic resonance imaging (MRI) findings in 100 consecutive NS patients who presented over a 15-year period. Clustering analysis (k-mode) was performed to evaluate co-occurrence of imaging findings. Non-enhancing white matter (NEWM) lesions were the most common imaging abnormality (56%), followed by leptomeningeal (47%) and pachymeningeal (32%) involvement. Other common manifestations included cranial nerve involvement (30%), parenchymal granulomas (27%), hypothalamic-pituitary-adrenal axis involvement (26%), and hydrocephalus (14%). Additionally, a higher prevalence of perivascular enhancement (23%), cerebrovascular events (including ischaemic and haemorrhagic events; 17%), and ependymal involvement (20%) were noted than recognised previously. Additional k-mode analysis was performed to explore underlying disease sub-clusters. This was evaluated for clusters varying between two though five (k=2-5). For k=4, the analysis revealed that the imaging findings may possibly be divided into disease sub-sets of four groups, each with varying distribution of imaging manifestations and clinical manifestations. Overall, NEWM lesions and meningeal involvement are the most common imaging manifestations of NS. The prevalence of perivascular enhancement, cerebrovascular events, and ependymal involvement is likely higher than reported previously. Additionally, different imaging findings in NS may cluster together and imaging subtypes in NS possibly exist.

MON-245 Brain Fog: An Important Cue to Neurosarcoidosis and Its Flare-Up?

Introduction:Sarcoidosis is a multisystem inflammatory disorder characterized by noncaseating granulomas in various organ systems, mainly the lung and lymphatic system. Neurosarcoidosis (NS) involving central or peripheral nervous system is uncommon and Hypothalamic-pituitary (HP) NS is rarer.Case:A 45-years-old African American man presented with a few days’ history of cognitive slowness (brain fog) and a sense of loss of direction. He was discharged a few months ago from another hospital after being admitted for shortness of breath and hypercalcemia of 13 mg/dl, which improved after hydration. CXR showed mediastinal and bilateral hilar enlargement. He was discharged home with outpatient pulmonary appointment but was readmitted to our hospital with altered mental status. Calcium level on this admission was 11.5 mg/dl. CT brain showed a sellar/suprasellar lesion, which was better visualized on MRI as enlargement and enhancement of pituitary gland, pituitary stalk, optic chiasm, left and right optic tract and nerves, and hypothalamus. He had left hemi-temporal field defect. Work up revealed inappropriately high normal 1,25 vitamin D, low PTH, PTrp and vitamin D. He has anterior hypopituitarism and mildly elevated prolactin. EBUS with mediastinal lymph node biopsy was non-diagnostic, however, excisional biopsy of mediastinal node showed non-caseating granuloma. ACE level, flow cytometry, infectious work up and serum IgG4 were normal.Discussion:NS may present as cranial nerve palsy, chronic headache with incidental HP mass and endocrine dysfunction such as diabetes insipidus, hyperprolactinemia, and anterior hypopituitarism. Visual deficits from optic atrophy or neuropathy; or change in vision from anterior uveitis are present in 41% of patients. Other non-specific presentations of NS include fatigue, cognitive difficulties (brain fog), such as impaired memory, slowed thinking, diminished attention and concentration. Hypercalcemia in sarcoidosis is due to increased intestinal absorption of calcium from increased 1,25 OH vitamin D. Though definitive diagnosis of NS is based on evidence of non-caseating granulomas from neural tissue, probable diagnosis can be made from clinical and radiologic characteristics, non-caseating granulomas at an extraneural site with no evidence of alternative disease. Steroid is the mainstay of treatment in NS and requires slow tapering. Other immunomodulators can be considered in worsening disease or patients with steroid adverse effect.Conclusion:Diagnosis of NS is challenging due to its rarity and difficult access to neural tissue for diagnosis. Though brain fog may not be specific for NS or its flare-up, additional neurological test or imaging should be considered especially in African American patients with hilar lymphadenopathy as 20% of NS patients may simply present with non-specific cognitive or behavioral complaints. ​

MRI findings in Neurosarcoidosis Patients with Headache as a Primary Presenting Symptom (1279)

MRI findings in Neurosarcoidosis Patients with Headache as a Primary Presenting Symptom (1279)

LncRNA SAMMSON overexpression distinguished glioblastoma patients from patients with diffuse neurosarcoidosis.

The MRI characteristics of diffuse neurosarcoidosis are similar to those of glioblastoma. Therefore, identification of novel biomarkers to distinguish these two diseases is needed. We found that lncRNA Survival Associated Mitochondrial Melanoma-Specific Oncogenic Non-Coding RNA (SAMMSON) was upregulated in plasma of glioblastoma patients but not in diffuse neurosarcoidosis patients comparing to healthy controls. Upregulated SAMMSON distinguished glioblastoma patients from diffuse neurosarcoidosis patients and healthy controls. MiR-622 in glioblastoma patients was inversely correlated with SAMMSON. SAMMSON overexpression caused the downregulated expression of miR-622 in glioblastoma cells, while miR-622 overexpression did not affect SAMMSON expression. SAMMSON overexpression mediated the increased proliferation rate of glioblastoma cells. MiR-622 overexpression played an opposite role and reduced the effects of SAMMSON overexpression. Therefore, plasma SAMMSON has diagnostic value for glioblastoma and SAMMSON overexpression may promote glioblastoma cell proliferation by downregulating miR-622.