Cerebrospinal fluid B-cell activating factor levels as a novel biomarker in patients with neurosarcoidosis.

OBJECTIVES: Neurosarcoidosis (NS) is a severe complication of sarcoidosis. Patients with NS often have poor outcomes. To improve both the quality of life and prognosis in patients with NS, accurate and reliable methods for early diagnosis and determining the efficacy of treatment are needed. This study aims to investigate B-cell-activating factor of the tumor necrosis factor family (BAFF) in cerebrospinal fluid (CSF) and elucidate the relationship between CSF BAFF levels and various parameters of NS. METHODS: We studied 20 patients with NS and 14 control subjects. We measured CSF BAFF levels in all subjects and investigated the relationship with clinical findings, serum and CSF measures, and magnetic resonance imaging (MRI) findings. RESULTS: CSF BAFF levels were significantly increased in patients with NS compared with controls (median 0.089 vs 0.04 ng/mL, p = 0.0005). CSF BAFF values were correlated with CSF findings-cell count, protein, angiotensin-converting enzyme, lysozyme, soluble interleukin-2 receptor, and immunoglobulin G-but not with serum parameters. CSF BAFF levels were especially higher in patients with abnormal intraparenchymal lesions of the brain and abnormal spinal MRI findings. CSF BAFF levels decreased significantly after immunosuppressive therapy. CONCLUSION: CSF BAFF may aid the quantitative evaluation of NS and may serve as a biomarker for this disease.

Inflammatory profiles in plasma and cerebrospinal fluid of patients with neurosarcoidosis.

METHODS: Cerebrospinal fluid (CSF) and plasma levels of 38 biomarkers from 20 neurosarcoidosis (NS) patients were compared to healthy controls (HC). RESULTS: In CSF, 25 biomarkers were significantly elevated compared to HC: IFNγ, TNFα, TNFß, 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. CONCLUSION: NS patients have profoundly elevated cytokines, chemokines, vascular angiogenesis, and vascular injury biomarkers in CSF and plasma.

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells.

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders.

Lymphocyte Immunophenotyping and CD4/CD8 Ratio in Cerebrospinal Fluid for the Diagnosis of Sarcoidosis-related Uveitis.

Background: This study aimed to assess the diagnostic relevance of CD4/CD8 ratio in cerebrospinal fluid (CSF) for the etiological diagnosis work-up of uveitis.Methods: We consecutively included patients who were referred to our department for the diagnostic workup of intermediate and/or posterior uveitis. Etiological diagnoses were established in a blind manner regarding CD4/CD8 ratio.Results: Fifty-two patients were included. A diagnosis of ocular sarcoidosis was made in 15 (29%) patients, 21% had another determined diagnosis while 50% remained of undetermined origin. Median CD4/CD8 ratio in CSF was 4.57 (IQR 3.39-5.47) in ocular sarcoidosis, 1.74 (1.60-3.18) in uveitis due to other determined cause (P = .008), and 2.83 (2.34-3.54) in those with uveitis of undetermined origin (P = .007). CD4/CD8 ratio >3.23 was associated with a diagnosis of ocular sarcoidosis.Conclusion: Determination of CD4/CD8 ratio in CSF can be useful for diagnosis work-up since a CD4/CD8 ratio >3.23 in CSF is associated with ocular sarcoidosis.

The Burden of Neurosarcoidosis: Essential Approaches to Early Diagnosis and Treatment.

Neurosarcoidosis (NS) is an often severe, destructive manifestation with a likely under-reported prevalence of 5 to 15% of sarcoidosis cases, and in its active phase demands timely treatment intervention. Clinical signs and symptoms of NS are variable and wide-ranging, depending on anatomical involvement. Cranial nerve dysfunction, cerebrospinal parenchymal disease, aseptic meningitis, and leptomeningeal disease are the most commonly recognized manifestations. However, non-organ-specific potentially neurologically driven symptoms, such as fatigue, cognitive dysfunction, and small fiber neuropathy, appear frequently.Heterogeneous clinical presentations and absence of any single conclusive test or biomarker render NS, and sarcoidosis itself, a challenging definitive diagnosis. Clinical suspicion of NS warrants a thorough systemic and neurologic evaluation hopefully resulting in supportive extraneural physical exam and/or tissue findings. Treatment targets the severity of the manifestation, with careful discernment of whether NS reflects active potentially reversible inflammatory granulomatous disease versus inactive postinflammatory damage whereby functional impairment is unlikely to be pharmacologically responsive. Non-organ-specific symptoms are poorly understood, challenging in deciphering reversibility and often identified too late to respond to conventional immunosuppressive/pharmacological treatment. Physical therapy, coping strategies, and stress reduction may benefit patients with all disease activity levels of NS.This publication provides an approach to screening, diagnosis, disease activity discernment, and pharmacological as well as nonpharmacological treatment interventions to reduce disability and protect health-related quality of life in NS.

Cerebrospinal fluid CD4+ /CD8+ ratio in diagnosing neurosarcoidosis.

OBJECTIVE: Neurosarcoidosis affects 5%-10% of patients with sarcoidosis. CD4+ /CD8+ ratio in bronchoalveolar lavage is included in diagnostic routine for pulmonary sarcoidosis. Previously, it has been suggested that a cerebrospinal fluid CD4+ /CD8+ ratio ≥5 can be an aid in diagnosing neurosarcoidosis. MATERIALS AND METHODS: This study included 66 cases where neurosarcoidosis was a differential diagnosis and hence subjected to the analysis of CSF CD4+ /CD8+ ratio by flow cytometry. RESULTS: Eleven cases of neurosarcoidosis, had a significantly higher median CSF CD4+ /CD8+ ratio than the other group, P = .024. The median CSF CD4+ /CD8+ ratio was 4.2, hence not reaching the suggested level of ≥5 for diagnosing neurosarcoidosis. When combined, the elevated CSF CD4+ /CD8+ ratio ≥5 and an elevated CSF lymphocyte count (>3 lymphocytes/uL) gave a positive predictive value of 57% and a high negative predictive value of 88%, with a specificity of 95% for neurosarcoidosis. CONCLUSION: The study confirms that increased CSF CD4+ /CD8+ ratio is associated with neurosarcoidosis but cannot alone distinguish the conditions from other neurological diagnoses. However, a ratio below <5 combined with an absence of pleocytosis in CSF yields a negative predictive value (NPV) of 88% suggesting a role for the analysis in differential diagnosing neuroinflammatory conditions.

Distinguishing neurosarcoidosis from multiple sclerosis based on CSF analysis: A retrospective study.

OBJECTIVE: To characterize a cohort of patients with neurosarcoidosis with particular focus on CSF analysis and to investigate whether CSF values could help in distinguishing it from multiple sclerosis (MS). METHODS: This retrospective cohort study enrolled 85 patients with a diagnosis of neurosarcoidosis (possible, probable, or definite). CSF total protein, white cell count, and angiotensin-converting enzyme levels were measured. CSF and serum oligoclonal immunoglobulin G (IgG) patterns were analyzed with the use of odds ratios and binary logistic regression. RESULTS: Eighty patients had a probable (nonneural positive histology) or definite (neural positive histology) diagnosis of neurosarcoidosis. Most frequent findings on MRI were leptomeningeal enhancement (35%) and white matter and spinal cord involvement (30% and 23%). PET scan showed avid areas in 74% of cases. CSF analysis frequently showed lymphocytosis (63%) and elevated protein (62%), but CSF-selective oligoclonal bands were rare (3%). Serum ACE levels were elevated in 51% of patients but in only 14% of those with isolated neurosarcoidosis. Elevated CSF ACE was not found in any patient. CONCLUSIONS: Large elevations in total protein, white cell count, and serum ACE occur in neurosarcoidosis but are rare in MS. The diagnostic use of these tests is, however, limited because minimal changes may occur in both. MS clinical mimics in neurosarcoidosis are not common, and intrathecal synthesis of oligoclonal IgG is a powerful discriminator because it is rare in neurosarcoidosis but occurs in 95% to 98% cases of MS. We suggest caution in making a diagnosis of neurosarcoidosis when intrathecal oligoclonal IgG synthesis is found.

Analysis of soluble interleukin-2 receptor as CSF biomarker for neurosarcoidosis.

OBJECTIVE: To systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis). METHODS: sIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis. RESULTS: Patients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis. CONCLUSIONS: CSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.

Clinical and MRI phenotypes of sarcoidosis-associated myelopathy.

OBJECTIVE: To determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder. METHODS: Patients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology. RESULTS: Of 62 included patients, 33 (53%) were male, and 30 (48%) were African American. SAM was the first clinical presentation of sarcoidosis in 49 patients (79%). Temporal profile of symptom evolution was chronic in 81%, with sensory symptoms most frequently reported (87%). CSF studies showed pleocytosis in 79% and CSF-restricted oligoclonal bands in 23% of samples tested. Four discrete patterns of lesion morphology were identified on spine MRI: longitudinally extensive myelitis (n = 28, 45%), short tumefactive myelitis (n = 14, 23%), spinal meningitis/meningoradiculitis (n = 14, 23%), and anterior myelitis associated with areas of disc degeneration (n = 6, 10%). Postgadolinium enhancement was seen in all but 1 patient during the acute phase. The most frequent enhancement pattern was dorsal subpial enhancement (n = 40), followed by meningeal/radicular enhancement (n = 23) and ventral subpial enhancement (n = 12). In 26 cases (42%), enhancement occurred at locations with coexisting structural changes (e.g., spondylosis). CONCLUSIONS: Recognition of the clinical features (chronically evolving myelopathy) and distinct MRI phenotypes (with enhancement in a subpial and/or meningeal pattern) seen in SAM can aid diagnosis of this disorder. Enhancement patterns suggest that SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress.

Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis.

Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS.

Differentiation between neurosarcoidosis and primary central nervous system vasculitis based on demographic, cerebrospinal and imaging features.

OBJECTIVES: Neurosarcoidosis (NS) and primary angiitis of central nervous system (PACNS) are inflammatory diseases affecting central nervous system, with overlapping clinical and pathological characteristics. Distinguishing these diseases is important given distinct therapeutic implications. In this study, we aimed to compare demographic, CSF and MRI characteristics between these two conditions. METHODS: All the clinical, CSF and laboratory characteristics at the time of presentation were retrieved from electronic medical records. Brain and/or spinal cord MRI performed near the time of presentation were blindly evaluated by two neuroradiologists. Data regarding involvement of pachy- and leptomeninges, basal meninges, cranial nerves, cerebral grey and white matter, and spinal cord were recorded for each patient. RESULTS: 78 patients with PACNS and 25 patients with NS were included in the study. Mean age of patients was 43.7 (±16.7) and 43.6 (±12.5) in PACNS and NS, respectively. African-American race was found to be associated with the diagnosis of NS rather than PACNS. Patients with PACNS had higher frequency of cerebral involvement, while patients with NS demonstrated more frequent spinal cord, basal meningeal and cranial nerve involvements. CONCLUSIONS: These findings suggest that MRI can be an efficient tool in distinguishing PACNS from NS. A follow-up study with a larger sample size would be required to validate our results.

Measurement of cerebrospinal fluid ACE level in aseptic meningitis: diagnostic?

Neurosarcoidosis (NS) is a rare disease, affecting only 3%-10% of patients with sarcoidosis. The clinical presentation can be protean and often represents a diagnostic challenge. Cerebrospinal fluid (CSF) ACE level has poor sensitivity, but high specificity for establishing a diagnosis of NS. We present a case of NS in a middle-aged African American woman who presented with dysphagia and dysphonia. An extensive radiological workup was negative for structural brain disease. CSF studies demonstrated lymphocyte predominant pleocytosis with an elevated ACE level. A diagnosis of possible neurosarcoidosis was made. She responded to systemic steroid therapy with complete resolution of her symptoms over the next five months. In the appropriate clinical setting, an elevated CSF ACE level could be of paramount importance for making a diagnosis of NS.

The cerebrospinal fluid CD4/CD8 ratio and interleukin-6 and -10 levels in neurosarcoidosis: a multicenter, pragmatic, comparative study.

BACKGROUND AND PURPOSE: Neurosarcoidosis is a rare inflammatory disorder of unknown cause. The aim of this study was to evaluate the value of T/B lymphocyte population counts and the concentrations of the cytokines interleukin (IL) 6 and IL-10 in the cerebrospinal fluid (CSF) of neurosarcoidosis patients. METHODS: A retrospective study CSF biomarkers was conducted in patients with neurosarcoidosis who underwent CSF analysis between 2012 and 2017 as well as various control populations. RESULTS: Forty-three patients with neurosarcoidosis, 14 with multiple sclerosis (MS) and 48 with other inflammatory disorders were analyzed. The CSF IL-6 levels were higher in sarcoidosis patients than in MS patients (median 8 vs. 3 pg/ml, P = 0.006). The CSF CD4/CD8 ratio was higher in sarcoidosis patients than in MS patients and in patients with other inflammatory disorders (median 3.18 vs. 2.36 and 2.10, respectively, P = 0.008). The CSF IL-6 level was higher in patients with active neurosarcoidosis than in non-active neurosarcoidosis patients (median 13 vs. 3 pg/ml, P = 0.0005). In patients with neurosarcoidosis, a CSF IL-6 concentration >50 pg/ml was associated with a higher risk of relapse or progression-free survival (hazard ratio 3.60; 95% confidence interval 1.78-23.14). A refractory neurosarcoidosis patient was treated with an anti-IL-6 monoclonal antibody that produced a complete neurological response. CONCLUSIONS: The CSF CD4/CD8 ratio and IL-6 concentration are increased in neurosarcoidosis compared to MS and other inflammatory disorders. A CSF IL-6 concentration >50 pg/ml is associated with relapse or progression of neurosarcoidosis. IL-10 levels may be elevated in neurosarcoidosis.

[Neurosarcoidosis - diagnosis, clinical picture and therapy]. / Neurosarkoidoza ­ diagnostyka, obraz kliniczny i leczenie.

Sarcoidosis (SA) is a granulomatous, multisystem disease of unknown etiology. Most often the disease affects lungs and mediastinal lymph nodes, but it may occur in other organs. Neurosarcoidosis (NS) more commonly occurs with other sarcoidosis forms, in 1% of cases it involves only nervous system. Symptomatic NS occurs but on autopsy study up to 25% of cases are confirmed. NS can affect central nervous system: the brain, spinal cord and peripheral nerves, and muscles. The diagnosis of neurosarcoidosis facilitates diagnostic criteria: histopathological, imaging and cerebrospinal fluid examination, and clinical symptoms. At present, there are no set standards for treatment of patients suffering from NS. Early therapy of symptomatic patients is recommended. Corticosteroids still are the first line of treatment for NS patients. In cases of steroids resistance, lack of their effectiveness or existence of contraindication to their use, immunosuppressant treatment is recommended. The latest NS algorithm with immunosuppressive treatment is discussed.

Search for biomarkers of neurosarcoidosis by proteomic analysis of cerebrospinal fluid.

Sarcoidosis is a systemic granulomatous disease, which mostly affects lung. Central nervous system can be affected causing a neurosarcoidosis in 5 to 15% of all sarcoidosis patients. The definitive diagnosis is established on histological examination of brain granulomas. Angiotensin converting enzyme is currently the most relevant biomarker to confirm a probable diagnosis; however, it lacks sensitivity and specificity. We aim to find novel biomarkers of neurosarcoidosis in cerebrospinal fluid (CSF) by proteomic analysis, combining two-dimension electrophoresis (2-DE) and mass spectrometry. We performed CSF proteomic profile of both patients (group S) and control subjects (group H). The statistical analysis of 2-D gels highlighted 42 spots significantly different between the two groups. Twenty-five spots were subjected to tryptic digestion; the peptides were analyzed by MALDI-TOF and MALDI-TOF-TOF, giving rise to 10 identifications. Among the identified proteins, low-molecular-mass-kininogen and vitamin-D-binding-protein were increased, while transthyretin was decreased. These proteins have probably an intrathecal source and could be interesting candidates. This study led to the identification of several proteins which can be used for the diagnosis and/or monitoring of neurosarcoidosis. These putative biomarkers have to be confirmed on a larger cohort and assessed for their sensitivity and specificity.

Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes.

INTRODUCTION: Neurosarcoidosis occurs in about 5% to 15% of patients with sarcoidosis. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients and to review the largest previously reported neurosarcoidosis case series. METHODS: This retrospective study enrolled all patients with the diagnosis of probable or definitive neurosarcoidosis according to Zajicek and Scolding criteria, followed at the neurology department of a tertiary center in Portugal from January 1989 to December 2015. RESULTS: A total of 15 patients presented a diagnosis of probable or definitive neurosarcoidosis, with a mean age at time of diagnosis of 38.5years. The presenting neurologic syndrome was isolated cranial neuropathy, aseptic meningitis, myelitis, brain parenchymal lesion, myelorradiculitis and meningomyelorradiculitis. MRI study most often presented different enhancing lesions and the CSF analysis commonly revealed a lymphocytic pleocytosis and raised proteins. Thirteen patients had histopathology confirmation of systemic sarcoidosis and one preformed a spinal cord biopsy. Corticosteroids was the most often used treatment alone or in combination with immunosuppressive drugs. After a mean follow-up of 86.1months, the majority of patients fully recovered to a mRankin 0. DISCUSSION: Fully comprehension of neurosarcoidosis is still a challenge due to its rarity and limited number of large published series, which renders the epidemiological study of this disease very difficult. In this study, the thoroughly medical records review and the summarize of previous published cohorts allow to add some information in the epidemiological and clinical knowledge of this entity.

Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of neurosarcoidosis.

BACKGROUND: Neurosarcoidosis (NS) is a rare condition that may mimic central nervous system (CNS) infection, neoplasia and other inflammatory disorders of the CNS such as multiple sclerosis, encephalitis and vasculitis. Diagnosis is challenging in cases with minimal or absent systemic involvement. Cerebrospinal fluid (CSF) angiotensin-converting enzyme (c-ACE) has been claimed as a valuable diagnostic tool for NS. However, there is little data evaluating its performance in routine clinical practice. FINDINGS: We performed a monocentric, retrospective, chart-based study including all patients investigated with a lumbar puncture and c-ACE dosage for suspected NS between 01/01/2006 and 31/12/2012 at the Geneva University Hospital. Receiver-operating characteristic (ROC) curve and area under the curve (AUC) were performed to calculate the optimal cut-off value of c-ACE and to determine the discriminative ability of c-ACE. Of the 440 patients included in the study, 9 were diagnosed with NS on the basis of tissue biopsy. Mean c-ACE was not significantly different between NS and non-NS patients. With a cut-off value of 2 (0-2 vs ≥3), sensitivity and specificity of c-ACE were 66.7% and 67.3%, respectively. CONCLUSIONS: In our clinical setting, the sensitivity and specificity of c-ACE for NS diagnosis were relatively poor and of little clinical utility.

Intrathecal BCR transcriptome in multiple sclerosis versus other neuroinflammation: Equally diverse and compartmentalized, but more mutated, biased and overlapping with the proteome.

The mechanisms driving the intrathecal synthesis of IgG in multiple sclerosis (MS) are unknown. We combined high-throughput sequencing of transcribed immunoglobulin heavy-chain variable (IGHV) genes and mass spectrometry to chart the diversity and compartmentalization of IgG-producing B cells in the cerebrospinal fluid (CSF) of MS patients and controls with other neuroinflammatory diseases. In both groups, a few clones dominated the intrathecal IGHV transcriptome. In most MS patients and some controls, dominant transcripts matched the CSF IgG. The IGHV transcripts in CSF of MS patients frequently carried IGHV4 genes and had more replacement mutations compared to controls. In both groups, dominant IGHV transcripts were identified within clusters of clonally related B cells that had identical or related IGHV transcripts in the blood. These findings suggest more pronounced affinity maturation, but an equal degree of diversity and compartmentalization of the intrathecal B-cell response in MS compared to other neuroinflammatory diseases.

Hypocretin Deficiency Associated with Narcolepsy Type 1 and Central Hypoventilation Syndrome in Neurosarcoidosis of the Hypothalamus.

We report a case of a 53-year-old man presenting with depressed alertness and severe excessive sleepiness in the setting of neurosarcoidosis. Neuroimaging demonstrated hypothalamic destruction due to sarcoidosis with a CSF hypocretin level of 0 pg/mL. The patient also experienced respiratory depression that presumably resulted from hypocretin-mediated hypothalamic dysfunction as a result of extensive diencephalic injury. This is a novel case, demonstrating both hypocretin deficiency syndrome, as well as respiratory dysfunction from destruction of hypocretin neurons and extensive destruction of key diencephalic structures secondary to the underlying neurosarcoidosis.