Neurosarcoidosis in Critical Care, Internal and Pulmonary Medicine: A Practical Approach

Abstract

Neurosarcoidosis is a rare but clinically significant manifestation of sarcoidosis, often presenting with diverse neurologic symptoms that can lead to permanent disability if left untreated. This review aims to provide internists, pulmonologists, non-neurologist clinicians, and critical care specialists with a structured, pragmatic approach to the evaluation, diagnosis, and management of neurosarcoidosis in two distinct patient groups: those with a known diagnosis of systemic sarcoidosis and those with no prior history of sarcoidosis. We emphasize the recognition of key acute clinical syndromes such as seizures, stroke, neuroendocrinopathy, hydrocephalus, meningeal disease, myelopathy, and infectious complications that may be encountered in emergency and critical care scenarios. The management approach, which includes first-line therapies such as glucocorticoids and immunomodulatory treatments such as TNF inhibitors and IL-6 inhibitors, is now accepted in the critical care setting to minimize the development of long-standing neurological complications associated with neurosarcoidosis. Furthermore, there is a critical need for a safe and effective transition to steroid-sparing medications for long-term disease control, while closely monitoring the risk for infections, such as tuberculosis and opportunistic infections, metabolic disturbances, and other complications. Given the significance of neurosarcoidosis as a severe manifestation of systemic sarcoidosis, a multidisciplinary approach is essential to effectively manage both neurological and systemic manifestations.

INTRODUCTION

Sarcoidosis is a multisystem disorder characterized by granulomatous inflammation, primarily affecting the lungs, skin, and eyes^1,2. Only about 5–26% of patients with systemic sarcoidosis develop neurological involvement, or neurosarcoidosis, a condition that can manifest with a variety of neurological symptoms, either independently or concomitantly with the classical pulmonary and lymphatic presentation of the disease.^3,4 The clinical manifestations of neurosarcoidosis are diverse, as patients can present with neuroinflammatory involvement of any compartment of the central nervous system (CNS), including the meninges, cranial nerves, spinal cord, or brain parenchyma. Compared to other sarcoidosis manifestations, patients with symptomatic neurosarcoidosis require intensive treatment to prevent morbidity, permanent disability, and death. Few patients develop isolated neurosarcoidosis, where clinical manifestations are purely neurologic without any systemic involvement, making a diagnosis of this condition particularly challenging.^3,5–7 Peripheral neuropathies and myopathies can also occur independently or be associated with CNS involvement. These can occur either in isolation or in combination with different neurological phenotypes.^8,9 The prevalence of sarcoidosis varies across different populations worldwide. In the United States, it is more frequently observed among African Americans and Caucasians of Northern European descent. Certain European countries have reported localized clusters with higher incidence rates.^10–12 In contrast, the prevalence of sarcoidosis in low and middle-income countries remains unclear. This uncertainty is mainly due to the high burden of infectious granulomatous disorders, such as tuberculosis, which can closely mimic sarcoidosis and often take precedence in clinical diagnosis.¹³

IMMUNOPATHOGENESIS OF SARCOIDOSIS

The pathological hallmark of sarcoidosis is the presence of non-caseating granulomas, accompanied by inflammation characterized by activated macrophages and lymphocytic infiltration, predominantly comprising CD4+ T-cells and B-cells.^14–16 Key players in this process are cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which are produced in large amounts by activated macrophages and contribute to the inflammatory response.^17,18 Single-cell transcriptomic analysis of peripheral immune cells underscores the central role of monocyte hyperactivation, along with dysregulation of CD4⁺ naïve and regulatory T cells and effector T-cell anergy.¹⁹ Non-caseating granulomata and inflammation may occur in any compartment of the CNS or the peripheral nervous system (PNS), resulting in focal or multifocal tissue damage that causes neurological dysfunction.⁴ Interestingly, despite the evidence of granulomatous inflammation as a central pathological feature, the etiological factors underlying sarcoidosis pathogenesis remain poorly understood. Similarly, the underlying factors contributing to neurological manifestations of sarcoidosis remain unknown, and it is still unclear whether racial, genetic, or other biological determinants influence the involvement of the CNS or PNS. Several hypotheses point to a potential role for infectious agents, environmental exposures (both infectious and non-infectious), and genetic predisposition.^20–23 These include exposure to mold, insecticides, metalworking fluids, firefighting environments, and inorganic dusts such as silica, beryllium, and aluminum. Additional risk factors include building materials and occupations in the healthcare sector. Notably, a higher incidence of sarcoidosis has been reported among World Trade Center firefighters, underscoring the potential pathogenic role of inhaled particulates in the development of the disease^24–26. Infections have also been linked to the pathogenesis of sarcoidosis. Tuberculosis and sarcoidosis exhibit notable immunological similarities. Mycobacterial antigens, such as heat shock proteins, the Ag85 complex, and catalase-peroxidase, can elicit pro-inflammatory T cell responses and cytokine profiles characteristic of both diseases. These findings support the hypothesis that mycobacterial components may act as infectious triggers in the pathogenesis of sarcoidosis.^23,27–29 The presence of geographic clusters and the increased risk observed among first- and second-degree relatives suggests environmental or infectious triggers may contribute to disease onset.^22,30 Genetic susceptibility also plays a significant role in sarcoidosis, potentially explaining its variable clinical manifestations across different ethnic groups.^12,31–33 Although studies on HLA associations in neurosarcoidosis are limited, evidence suggests that ancestry-specific genetic risk factors exist. Beyond HLA-related associations, several non-HLA genetic variants have been linked to sarcoidosis susceptibility and organ-specific involvement, although few are specifically associated with neurosarcoidosis. One notable exception is a variant in ZNF592 (rs75652600), which is significantly associated with neurosarcoidosis in Black patients. Other implicated loci include BLOC1S1 (previously reported as BOTCH4) and the 15q25 region.^19,34–36

CLINICAL APPROACH TO THE EVALUATION OF NEUROSARCOIDOSIS

The clinical presentations of neurosarcoidosis are highly heterogeneous, reflecting the potential for focal or multifocal inflammation that can affect the CNS or PNS (Table 1). Clinical investigation of patients with suspected neurosarcoidosis requires a comprehensive assessment of both neurological symptoms and systemic manifestations. While neurological symptoms associated with neurosarcoidosis can emerge in patients with a confirmed diagnosis of sarcoidosis, it is essential to recognize that neurological symptoms of neurosarcoidosis may represent the initial manifestation of sarcoidosis in patients with an unknown history of the disease. This is particularly relevant for non-neurologists and critical care specialists, who should be attentive in identifying potential neurological presentations of sarcoidosis. The evaluation and diagnosis of suspected neurosarcoidosis can be approached through two primary clinical scenarios: First, patients with a known diagnosis of sarcoidosis who develop new neurological symptoms suggestive of CNS or PNS involvement. Second, patients without a prior history of sarcoidosis who present with acute or subacute-onset neurological symptoms and whose clinical features of a neuroinflammatory disorder should consider neurosarcoidosis among the potential causes. The focus of this review is on CNS involvement and phenotypes that may lead to critical care situations (Table 1).

Table 1.

CLINICAL PHENOTYPES OF NEUROSARCOIDOSIS AND EMERGENCY SITUATIONS

Clinical Phenotype	Neurological presentation	Clinical profile	Clinical course	Acute presentations/Emergencies
Meningeal forms	Aseptic or recurrent meningitis Basal meningitis Chronic meningitis Pachymeningitis Dural tumor-like sarcoid lesions	Headaches Fevers Nausea and vomiting Increase intracranial pressure Hydrocephalus Papilledema Cranial nerve palsies, mono- or multiple Seizures	Subacute, recurrent or chronic	Acute hydrocephalus Increased intracranial pressure Subfalcine herniation Seizures. 1,2
Cranial neuropathies	Facial paralysis Optic neuropathy Multiple cranial neuropathies	Mono- or multiple cranial nerve palsies Facial weakness Diplopia Visual blurriness Vestibular symptoms	Acute, subacute, Monophasic, or recurrent	Optic neuritis/blindness Acute/subacute hearing loss Vestibular dysfunction leading gait disturbance Lower cranial nerve dysfunction leading to swallowing difficulties, respiratory compromise.3,4
Encephalitic forms	Focal encephalitis Focal or multifocal leukoencephalitis Tumor-like sarcoid lesions	Headaches Psychosis Seizures Neuroendocrine manifestations Focal neurological symptoms	Subacute, recurrent, or chronic	Seizures and status epilepticus Acute confusional states Cerebral edema with risk of herniation Adrenal crisis/insufficiency.5,6
Myelopathic form	Subacute Progressive myelopathy	Gait disturbances Paraparesis/Paraplegia Bladder dysfunction Paresthesias/*dysesthesias Sensory level	Subacute, Monophasic, recurrent, or chronic	Paralysis Cauda equina syndrome Dysautonomia Respiratory compromise.2,7–9

^1.Kidd DP. Sarcoidosis of the central nervous system: clinical features, imaging, and CSF results. Journal of neurology. Aug 2018;265(8):1906–1915. doi:10.1007/s00415-018-8928-2

^2.Nolte JYC, Ten Dam L, van de Beek D, Brouwer MC. Clinical characteristics and outcome of neurosarcoidosis-associated myelitis: A retrospective cohort study and review of the literature. Eur J Neurol. Jun 2022;29(6):1763–1770. doi:10.1111/ene.15295

^3.Chakales PA, Herman MC, Chien LC, Hutto SK. Pachymeningitis in Biopsy-Proven Sarcoidosis: Clinical Course, Radiographic Findings, Response to Treatment, and Long-term Outcomes. Neurology(R) neuroimmunology & neuroinflammation. Nov 2022;9(6)doi:10.1212/nxi.0000000000200028

^4.Barreras P, Stern BJ. Clinical features and diagnosis of neurosarcoidosis - review article. Journal of neuroimmunology. Jul 15 2022;368:577871. doi:10.1016/j.jneuroim.2022.577871

^5.Berntsson SG, Elmgren A, Gudjonsson O, Grabowska A, Landtblom AM, Moraes-Fontes MF. A comprehensive diagnostic approach in suspected neurosarcoidosis. Sci Rep. Apr 21 2023;13(1):6539. doi:10.1038/s41598-023-33631-z

^6.Bou GA, El Sammak S, Chien LC, Cavanagh JJ, Hutto SK. Tumefactive brain parenchymal neurosarcoidosis. Journal of neurology. Sep 2023;270(9):4368–4376. doi:10.1007/s00415-023-11782-3

^7.Murphy OC, Salazar-Camelo A, Jimenez JA, et al. Clinical and MRI phenotypes of sarcoidosis-associated myelopathy. Neurology(R) neuroimmunology & neuroinflammation. Jul 2 2020;7(4)doi:10.1212/nxi.0000000000000722

^8.Al-Hader R, Nofar J, Mohamedelkhair A, Affan M, Schultz LR, Cerghet M. A Comprehensive Characterization of Patients with Spinal Cord Neurosarcoidosis: A Single Center Cross-Sectional Study of Clinical Outcomes. J Clin Med. Aug 27 2024;13(17)doi:10.3390/jcm13175069

^9.Bou GA, Garcia-Santibanez R, Castilho AJ, Hutto SK. Neurosarcoidosis of the Cauda Equina: Clinical Course, Radiographic and Electrodiagnostic Findings, Response to Treatment, and Outcomes. Neurology(R) neuroimmunology & neuroinflammation. Jul 2022;9(4)doi:10.1212/nxi.0000000000001170

The diagnostic strategy for each scenario is outlined in Figure 1. In the first scenario, for patients with an already biopsy-proven diagnosis of systemic sarcoidosis, the diagnostic approach for establishing a diagnosis of neurosarcoidosis is often more straightforward, as there is already a documentation of extra-neural sarcoidosis involvement, shifting the focus of assessment mostly to determining the extent and pattern of nervous system involvement and clinical phenotypes⁵. In the second scenario, for patients without a prior diagnosis of sarcoidosis who present with neurological symptoms suggestive of the disease, diagnostic strategies should aim to establish the certainty of the diagnosis and the differentiation from other neuroinflammatory or neoplastic disorders that may mimic neurosarcoidosis (Table 2). Once such mimickers are ruled out, the next critical steps are to assess both the systemic involvement and the nature of the neurological abnormalities. Because pulmonary and intrathoracic lymph node involvement are the most common systemic manifestations of sarcoidosis, even in those who present initially with neurological manifestations, a focused pulmonary evaluation is essential. There are co-occurring subtle symptoms and signs, such as chronic coughs, skin lesions, uveitis, and constitutional symptoms, that may also raise suspicion.^1,2,37 Imaging modalities, such as chest CT scan and fluorodeoxyglucose positron emission tomography (FDG-PET), are valuable tools for detecting active disease and guiding biopsy site selection. When radiologic evidence of hilar or mediastinal lymphadenopathy or pulmonary lesions is present, tissue biopsy is strongly recommended to confirm the diagnosis pathologically.¹ If a biopsy is feasible, pulmonologists typically target thoracic lymph nodes using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy, or transbronchial lung biopsy, especially when parenchymal abnormalities are seen on imaging. Beyond the neurological examination, a comprehensive physical exam is essential to identify systemic signs of sarcoidosis. Findings such as cutaneous lesions (e.g., lupus pernio or subcutaneous nodules), lymphadenopathy, or hepatosplenomegaly may suggest systemic involvement and guide biopsy efforts.¹ These lesions may provide the tissue necessary for pathological confirmation of sarcoidosis. For patients with a history of palpitations, arrhythmias, or other cardiac symptoms, evaluation may include echocardiography or cardiac MRI to detect sarcoid-related myocardial involvement.^38,39 Similarly, ophthalmologic assessment is critical in all care settings, including intensive care units, for detecting uveitis or other retinal pathologies that may support the diagnosis of systemic sarcoidosis.^40,41 A challenging situation is the patient with unique neurological manifestations that emerge without evidence of systemic disease, in which neurosarcoidosis may be the sole manifestation or an isolated neurosarcoidosis. In such cases, a tissue biopsy (e.g., meninges, dura mater, or brain) may be required to document pathological changes consistent with granulomatous inflammation.

Figure 1. Diagnostic Approach in a Patient with Suspected Neurosarcoidosis.

The evaluation of suspected neurosarcoidosis follows two main clinical pathways. The first includes patients with an established diagnosis of systemic sarcoidosis who develop new neurological manifestations suggestive of CNS or PNS involvement. The second involves patients without a prior history of sarcoidosis who present with acute or subacute neuroinflammatory symptoms in whom neurosarcoidosis is considered among the differential diagnoses. Diagnostic strategies should aim to confirm disease certainty and distinguish neurosarcoidosis from other inflammatory or neoplastic mimics as outlined in Table 2. The consensus diagnostic criteria for neurosarcoidosis define three categories of neurosarcoidosis diagnosis based on the presence of pathological evidence of CNS involvement (Definite), extra-neural (Probable), or just clinical (Possible) evidence.⁶²

Abbreviations: WBC: white blood cell count; AQP4: Aquaporin-4; MOG: Myelin oligodendroglial glycoprotein; TB: Tuberculosis; ECHO: echocardiogram; FDG-PET: Fluoro-deoxyglucose-Positron Emission Tomography.

Table 2.

CLINIC CONDITIONS THAT MIMIC NEUROSARCOIDOSIS

Condition	How It Mimics Neurosarcoidosis	How to Differentiate	Ref.
Neuroinflammatory Disorders
Multiple Sclerosis (MS)	CNS ovoid lesions, optic neuritis, myelitis, cranial neuropathies	Periventricular/juxtacortical lesions on MRI, central venous sign, oligoclonal bands on CSF, lack of systemic findings or radiological evidence of hilar lymphadenopathies or lung granulomata, no granulomas on biopsy	1–3
Neuromyelitis Optica (NMO)	Longitudinally extensive cord lesions, optic neuritis, area postrema syndrome (e.g., intractable hiccups, nausea/vomiting), acute brainstem syndrome	Serum AQP4-IgG seropositivity (cell-based assay), lack of systemic findings, bilateral longitudinal extensive optic neuritis, brain MRI may show peri-ependymal, diencephalic, area postrema involvement. No radiological evidence of hilar lymphadenopathies or lung granulomata	3–5
Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD)	Tumefactive white matter lesions, meningitis, longitudinally extensive lesions, short-segment myelitis, intracranial lesions, optic neuritis	Serum MOG-IgG seropositivity (cell-based assay), optic neuritis is often severe and bilateral, cortical and subcortical lesions are more common, lack of systemic findings.	3,5–8
Neuro-Behçet’s Disease	Meningoencephalitis, brainstem and cranial nerve palsies, myelitis	Brain or brainstem lesions associated with veno-occlusive disease. History of oral/genital ulcers, positive pathergy test, HLA-B51 positivity, CSF neutrophilic pleocytosis	9
ANCA-associated vasculitis (Wegener’s granulomatosis)	Dural-based enhancing lesions, Ischemic or hemorrhagic infarcts (often small vessel distribution), pituitary involvement. Pulmonary and dermatological involvement.	Focal or extensive pachymeningitis, ENT involvement (sinusitis, nasal septal perforation), pulmonary cavitations, biopsy showing necrotizing granulomas, c-ANCA (PR3+) positive,	10,11
Secondary CNS Vasculitis (infectious, autoimmune, neoplastic)	Multifocal infarcts, meningeal enhancement, encephalopathy	Infection (VZV, TB, Hepatitis C), systemic autoimmune disease (SLE, Behcet’s), or malignancy, vessel (beading/segmental narrowing), and/or irregularities on angiogram, infarcts in multiple vascular territories	11
IgG4-related disorders	Cranial neuropathies, Pachymeningeal involvement	Pachymeningitis, predominantly dural or orbit involvement, retroperitoneal fibrosis, pancreatitis or sclerosing cholangitis, lymphoplasmacytic infiltrate, IgG4+ plasma cells on biopsy	12,13
Neuroinfectious Disorders
CNS Tuberculosis	Leptomeningeal enhancement, frequently basal, multiple nodular or ring-enhancing lesions in brain, cranial neuropathies, longitudinally extensive myelitis. Sarcoidosis patients may have positive Quantiferon-TB gold test (T-spot)*	CSF cultures, PCR, TB stains, antigen/antibody testing; caseating (vs. noncaseating) granulomas on biopsy, history of travel or residing in endemic areas.	14–16
CNS fungal infections (e.g., histoplasmosis, blastomycosis)	Leptomeningeal enhancement, cranial neuropathies, hydrocephalus, basilar meningitis	Immunosuppressed host, CSF subacute fevers, positive fungal cultures/antigens	17
Subacute, chronic or recurrent meningitis (e.g., cryptococcus, HSV-associated meningitis)	Basilar meningitis, hydrocephalus, cranial neuropathies	Immunosuppression (steroids, HIV), CSF India ink, cryptococcal antigen positive, gelatinous pseudocysts on imaging	17–19
Neurosyphilis	Meningitis, cranial nerve palsies, myelopathy	Positive serum RPR/VDRL and CSF-VDRL, classic clinical features (e.g., Tabes dorsalis, Argyll Robertson pupils)	20
CNS Tumors/Cancer-Associated CNS Disorders
CNS Lymphoma (Primary/Secondary)	Enhancing brain lesions, leptomeningeal disease, cranial neuropathies	CSF cytology/flow cytometry, PET-CT with hypermetabolic masses, biopsy showing malignant lymphoid cells	21
Meningiomas	Dura or meningeal-based enhancing mass lesions, cranial neuropathies, if skull-based is involved	Well-circumscribed mass, solitary, slow-growing, lack of systemic involvement, or CSF abnormalities	22,23
Metastatic Tumors (Leptomeningeal carcinomatosis)	Multiple cranial neuropathies, leptomeningeal enhancement, cauda equina involvement	Known primary malignancy (lung, breast, melanoma, lymphoma); CSF cytology positive, flow cytometry, FDG-PET findings	24

^1.Filippi M, Preziosa P, Arnold DL, et al. Present and future of the diagnostic work-up of multiple sclerosis: the imaging perspective. Journal of neurology. Mar 2023;270(3):1286–1299. doi:10.1007/s00415-022-11488-y

^2.Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. The New England journal of medicine. Jan 11 2018;378(2):169–180. doi:10.1056/NEJMra1401483

^3.Filippi M, Preziosa P, Margoni M, Rocca MA. Diagnostic Criteria for Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorders, and Myelin Oligodendrocyte Glycoprotein-immunoglobulin G-associated Disease. Neuroimaging clinics of North America. Aug 2024;34(3):293–316. doi:10.1016/j.nic.2024.03.001

^4.Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. Jul 14 2015;85(2):177–89. doi:10.1212/wnl.0000000000001729

^5.Sechi E. NMOSD and MOGAD. Continuum (Minneapolis, Minn). Aug 1 2024;30(4):1052–1087. doi:10.1212/con.0000000000001454

^6.Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. The Lancet Neurology. Mar 2023;22(3):268–282. doi:10.1016/s1474-4422(22)00431-8

^7.Varley JA, Champsas D, Prossor T, et al. Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children. Neurology. Jul 2024;103(1):e209321. doi:10.1212/wnl.0000000000209321

^8.Syc-Mazurek SB, Cacciaguerra L, Tajfirouz DA, et al. MRI characteristics during attack and remission distinguish patients with MOG antibody-associated disease from multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry. Jul 20 2025;doi:10.1136/jnnp-2025-336684

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^11.Nehme A, Boulanger M, Aouba A, et al. Diagnostic and therapeutic approach to adult central nervous system vasculitis. Revue neurologique. Dec 2022;178(10):1041–1054. doi:10.1016/j.neurol.2022.05.003

^12.Stone JH, Zen Y, Deshpande V. IgG4-related disease. The New England journal of medicine. Feb 9 2012;366(6):539–51. doi:10.1056/NEJMra1104650

^13.Terrim S, Mahler JV, Filho FVM, et al. Clinical Presentation, Investigation Findings, and Outcomes of IgG4-Related Pachymeningitis: A Systematic Review. JAMA Neurol. Feb 1 2025;82(2):193–199. doi:10.1001/jamaneurol.2024.3947

^14.Saylor D. Neurologic Complications of Tuberculosis. Continuum (Minneapolis, Minn). Aug 1 2021;27(4):992–1017. doi:10.1212/con.0000000000001005

^15.Garg RK. Tuberculosis of the central nervous system: current concepts in diagnosis and treatment. Current opinion in neurology. Aug 1 2025;38(4):406–413. doi:10.1097/wco.0000000000001358

^16.Mertiri L, Freiling JT, Desai NK, Kralik SF, Huisman T. Pediatric and adult meningeal, parenchymal, and spinal tuberculosis: A neuroimaging review. J Neuroimaging. Mar-Apr 2024;34(2):179–194. doi:10.1111/jon.13177

^17.Nathan CL, Emmert BE, Nelson E, Berger JR. CNS fungal infections: A review. Journal of the neurological sciences. 2021/03/15/ 2021;422:117325. doi:https://doi.org/10.1016/j.jns.2021.117325

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^19.Aksamit AJ. Chronic Meningitis. The New England journal of medicine. Sep 2 2021;385(10):930–936. doi:10.1056/NEJMra2032996

^20.Hamill MM, Ghanem KG, Tuddenham S. State-of-the-Art Review: Neurosyphilis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. May 15 2024;78(5):e57-e68. doi:10.1093/cid/ciad437

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^24.Nguyen A, Nguyen A, Dada OT, et al. Leptomeningeal Metastasis: A Review of the Pathophysiology, Diagnostic Methodology, and Therapeutic Landscape. Current Oncology. 2023;30(6):5906–5931.

Clinical strategies for evaluation of neurosarcoidosis.

Neuroimaging.

Evaluation of the entire CNS axis with MRI of the brain and spinal cord is essential for assessing disease burden and localization. Gadolinium-enhanced MRI is particularly valuable for identifying meningeal involvement (e.g., leptomeningeal or dural enhancement) and active inflammation in encephalitic or myelopathic forms^3,4. Specific characteristics include leptomeningeal enhancement, parenchymal granulomatous lesions that often present as nodular enhancing lesions, or cranial nerve or hypothalamic-pituitary involvement, and longitudinal extensive myelitis or involvement of the posterior columns, which may alert to the presence of neurosarcoidosis.^42,43 A head CT scan may be used in acute or emergency settings when an MRI is not feasible. This imaging approach is likely the first line of imaging assessment in emergencies such as suspected cerebrovascular disease^44,45 or acute mental status changes that may be associated with hydrocephalus.⁴⁶

Blood biomarkers.

Serum markers, including angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), serum amyloid A (SAA), chitotriosidase, and YKL-40 (also known as chitinase-3-like protein 1, CHI3L1), have been studied as potential diagnostic markers for sarcoidosis.^47–50 However, their specificity and diagnostic utility for neurosarcoidosis are poor. While sIL-2R appears to be a supportive biomarker for diagnosing sarcoidosis, severity of inflammatory response, and for assessing disease chronicity, it lacks discriminatory power compared with other pulmonary inflammatory disorders.^47,51,52

Cerebrospinal fluid (CSF).

The study of CSF is critical for assessing CNS inflammatory activity and ruling out alternative diagnoses such as infectious (e.g., tuberculosis, fungal) or neoplastic meningitis.^53–55 Findings may include pleocytosis, elevated protein concentration, decreased glucose levels, and an increased IgG index^4,8,56,57. In subsets of patients with neurosarcoidosis, oligoclonal bands (OCBs) may be present, either exclusively in CSF (pattern 2) or in both CSF and serum (pattern 3). Importantly, CSF-ACE levels have limited diagnostic utility due to their low sensitivity and specificity and should not be used as a diagnostic biomarker for neurosarcoidosis.^57,58 High CSF concentration of sIL-2R may help to distinguish neurosarcoidosis from other neuroinflammatory disorders, but lacks a discriminative power.^51,59

CNS Tissue biopsy.

In selected cases, biopsy of CNS (e.g., brain, dura, or meninges) or PNS tissues (e.g., peripheral nerve, muscle, or skin for small fiber neuropathy) may be pursued to confirm the diagnosis. As with any invasive procedure, the decision to obtain neural tissue should be carefully weighed, particularly when a pathological diagnosis is essential for guiding treatment and cannot be established through less invasive means. In most cases, a probable diagnosis of neurosarcoidosis is sufficient to initiate therapy. In patients presenting with neuromuscular forms of neurosarcoidosis, such as peripheral neuropathy, sural nerve biopsies have a low diagnostic yield. However, muscle biopsies guided by ultrasound or MRI can be helpful in detecting granulomatous inflammatory myopathies associated with sarcoidosis.^60,61

Diagnostic Criteria for Neurosarcoidosis

In 2018, a multidisciplinary expert panel proposed a consensus diagnostic framework⁶², which defines three categories of neurosarcoidosis diagnosis: 1) Definite diagnosis of neurosarcoidosis is established in patients when the following criteria are met: the clinical presentation is consistent with a neurological form of sarcoidosis as described in Table 1. Supportive evidence is present in clinical studies, including neuroimaging (e.g., MRI of the brain and/or spinal cord) and/or CSF analysis, and other potential causes of neurological dysfunction have been rigorously excluded; and most importantly, a pathological confirmation of granulomatous inflammation is obtained from CNS or PNS tissue (e.g., brain, meninges, dura, peripheral nerve, or muscle). The diagnosis of definite neurosarcoidosis is further subcategorized as Type A, when systemic (extraneural) sarcoidosis is present, or Type B, when no evidence of systemic sarcoidosis is found (isolated CNS sarcoidosis). 2) A probable diagnosis of neurosarcoidosis may be established if the clinical profile is consistent with any of the neurological forms of the disease, supported by neuroimaging studies and/or CSF, associated with pathological documentation by biopsy of non-neural tissues (e.g., lymph node, lung, skin, sclera, liver) and after rigorous exclusion of other potential causes of neurological dysfunction (Table 2). 3) A possible diagnosis of neurosarcoidosis may be established if the clinical profile is consistent with any of the forms of neurosarcoidosis supported by neuroimaging studies and/or CSF, and the rigorous exclusion of other possible causes of neurological dysfunction; however, pathological confirmation by tissue biopsy is absent (Figure 1).

CLINICAL SYNDROMES AND PHENOTYPES IN NEUROSARCOIDOSIS

Meningeal forms.

Subacute, chronic, or relapsing “aseptic” meningitis and pachymeningitis are common manifestations of the meningeal forms of neurosarcoidosis. Accurate diagnosis requires a thorough clinical assessment, gadolinium-enhanced brain MRI, and comprehensive CSF analysis to exclude other conditions, such as autoimmune neuroinflammatory disorders (e.g., MOGAD)⁶³, infectious meningitis (e.g., tuberculous, fungal, viral)⁵⁴ or neoplastic meningitis⁵⁵. Patients with meningitis often experience headaches, neck stiffness, and altered mental status, symptoms that indicate meningeal inflammation. Aseptic meningitis is a common presentation, characterized by persistent or recurrent symptoms without an identifiable infectious cause. Frequently, meningeal forms of neurosarcoidosis overlap with cranial nerve manifestations, encephalitis and/or may lead to hydrocephalus. MRI may demonstrate leptomeningeal enhancement, which is often diffuse and may appear “nodular.” Pachymeningeal disease may present in various forms, including focal dural-based masses that mimic tumors, such as meningiomas, or focal dural thickening, as seen in cavernous sinus mass lesions. Alternatively, it may manifest as more diffuse pachymeningeal disease, characterized by thickening and enhancement of the dura mater. Sarcoid-related pachymeningitis may have a predilection for specific dural sites, including the falx cerebri, anterior and middle cranial fossae, and tentorium cerebelli.^42,64 These cases often proved refractory to conventional immunosuppressive therapies and require treatment with immunomodulatory agents such as TNF inhibitors. Occasionally, spinal arachnoiditis may be present either associated or isolated from myelopathic forms of neurosarcoidosis.⁴³

Cranial neuropathies.

Involvement of the cranial nerves is a common clinical manifestation of neurosarcoidosis and may present acutely, either as a monophasic episode or in a recurrent pattern. Bilateral facial paralysis and optic neuritis are frequent manifestations of the cranial neuropathy form of neurosarcoidosis. In most cases, facial palsy and other cranial nerve deficits are associated with basal meningitis.^3,4,8,42 They are thought to result from perineural inflammation rather than intra-axial, axonal, or demyelinating lesions. Other cranial nerves, such as the oculomotor, vestibular, and lower cranial nerves, may also be affected. Optic nerve involvement can pose diagnostic challenges, particularly when accompanied by encephalitic features that mimic multiple sclerosis, NMO or MOGAD. A thorough neuro-ophthalmological evaluation is essential in patients with visual symptoms to assess for uveitis, iridocyclitis, or other ocular manifestations.^40,65–67 In general, cranial neuropathies respond well to corticosteroid therapy, although optic and vestibulocochlear involvement may follow a relapsing-remitting or chronic course. MRI will demonstrate enhancement of the optic nerve sheath, causing perineuritis, or the optic nerve, causing optic neuritis.^65,68 Involvement of the vestibulo-chochlear nerve has been under-reported, but patients report vertigo and hearing loss. Less commonly, the glossopharyngeal (cranial nerve IX), vagus nerve (cranial nerve X), and hypoglossal nerve (cranial nerve XII) lead to dysphagia, dysphonia, and tongue dysfunction.^69–71

Encephalitic forms.

Focal encephalitis, leukoencephalitis, and multifocal white matter involvement represent aggressive forms of neurosarcoidosis, typically associated with subacute, relapsing-remitting, or chronic clinical courses. Encephalitic forms also may present acutely with seizures, headache, signs of increased intracranial pressure, psychosis, motor deficits, cognitive decline, and other focal neurological symptoms.^3,4,8,42,72 These focal or multifocal leukoencephalitic forms can closely mimic the clinical and MRI features of neuroinflammatory or demyelinating disorders such as multiple sclerosis, MOGAD, NMO, neuro-Behçet’s, autoinflammatory neurological disorders (e.g., CTLA4 haplotype), or even brain neoplasms such as lymphomas or gliomas. Therefore, in patients presenting with suspected demyelinating disorders or neuroinflammatory, sarcoidosis should be considered and ruled out before confirming a diagnosis. Some focal encephalitic variants of neurosarcoidosis are particularly aggressive, showing limited response to corticosteroids and requiring more intensive immunosuppressive therapy.⁷³ A subset of patients develops neuroendocrine manifestations due to localized granulomatous inflammation in the infundibular, peri-infundibular, and suprasellar regions. This variant of neurosarcoidosis is sometimes recognized as a unique form, a neuroendocrine form, as these lesions may progress to hypothalamic dysfunction, focal encephalitis, or hypophysitis. Clinically, they often present with hormonal deficiencies, most notably hypogonadism, central diabetes insipidus, or other symptoms such as sleep disturbances, bradycardia, and hypothermia.^74,75 Although the inflammatory process in this form is frequently monophasic and subacute, it can lead to persistent endocrine dysfunction, necessitating long-term hormonal replacement and close endocrinological monitoring^73,76.

Myelopathic forms.

Sarcoid-associated myelopathy may present in various ways and can pose significant diagnostic challenges, particularly in the absence of a known history of systemic sarcoidosis. These cases often manifest as subacute or slowly progressive myelopathies with both motor and sensory symptoms. A presumptive diagnosis of sarcoid myelopathy may be considered in patients with a history of systemic sarcoidosis who present with clinical signs of myelopathy and corresponding MRI evidence of focal or multifocal intra-axial spinal cord lesions^43,77,78. However, it is very frequent that sarcoid-associated myelopathy or myelitis presents as the first manifestation of sarcoidosis and requires an extensive assessment to differentiate from other disorders, such as inflammatory myelopathies in NMO, MOGAD, or demyelinating diseases, or even spondylotic spine disease myelopathy^43,79. Frequent features of sarcoid-associated myelopathy include longitudinally extensive myelitis, when the cord lesion spans three or more vertebral segments and is associated with gadolinium enhancement. Other imaging characteristics include short tumefactive myelitis and spinal meningitis or meningoradiculitis^43,77,78.

NEUROLOGICAL EMERGENCIES IN NEUROSARCOIDOSIS

Neurosarcoidosis is associated with potentially life-threatening complications requiring critical care management. Due to the broad spectrum of clinical syndromes in neurosarcoidosis and the potential for rapid deterioration, especially in the context of multi-organ sarcoid involvement or isolated CNS involvement, it is essential that non-neurologist clinicians, including critical care specialists, be aware of the acute neurological emergencies that may be present in patients with known history of sarcoidosis or those with unexplained neurological symptoms where sarcoidosis may not yet been identified. Emergency and critical care management may be required when patients with a known history of sarcoidosis or neurosarcoidosis experience abrupt changes in mental status or other neurological disturbances. Conditions such as acute hydrocephalus, seizures or status epilepticus, metabolic disturbances, and pituitary-hypothalamic dysfunction are the most common causes of such complications.^8,46,73,76 The most frequent neurological emergencies in the setting of sarcoidosis, along with the various clinical CNS phenotypes of neurosarcoidosis, are outlined in Table 1.

Critical Care Monitoring and Supportive Measures

In ICU settings, all patients with concerns for possible neurosarcoidosis-related complications must have serial monitoring of the Glasgow Coma Scale (GCS) and pupillary responses, and frequent neurological assessments.⁸⁰ Additionally, intubation with mechanical ventilation must be considered for airway protection in patients with status epilepticus, critical brainstem involvement, or acute hydrocephalus. If concerns are raised regarding hydrocephalus or cerebral edema during examination and imaging, ICP monitoring is necessary.^81,82 Frequent laboratory monitoring for syndrome of inappropriate antidiuretic hormone secretion (SIADH) and diabetes insipidus is highly encouraged, including sodium, glucose, and cortisol levels. Treatment of patients with neurosarcoidosis in ICU settings will require a multidisciplinary approach, including critical care specialists for acute management of complications, neurology for imaging, seizure management, and immunosuppressive strategy, neurosurgery for hydrocephalus management, endocrinology for diabetes insipidus and adrenal insufficiency management, and infectious diseases for infection prophylaxis and treatment.³

Hydrocephalus.

Because leptomeningeal inflammation is a frequent presentation of neurosarcoidosis, hydrocephalus may emerge as a complication of this form of the disease.^8,46,83 In such cases, granulomatous inflammation impair CSF reabsorption at the arachnoid villi or obstruct CSF outflow, leading to progressive hydrocephalus and elevated intracranial pressure, which can present acutely or subacutely (Figure 2).^8,76 Patients presenting with altered mental status or reduced consciousness, acute hydrocephalus must remain high on the differential diagnosis, and an urgent head CT must be obtained. Special caution is needed when performing lumbar punctures in patients with hydrocephalus, as these procedures can increase the risk of decompensation and cerebellar tonsillar herniation. When hydrocephalus is identified in patients with neurosarcoidosis, neurology and neurosurgery consultants must be made aware for consideration of emergency CSF diversion by placing an external ventricular drain and initiating corticosteroids urgently. Some patients may require emergency ventriculostomy or ventriculoperitoneal shunting, but such neurosurgical interventions must be carefully evaluated on a case-by-case basis.^46,83,84

Figure 2. Hydrocephalus in Neurosarcoidosis.

Hydrocephalus is a frequent neurological emergency in subjects with neurosarcoidosis. A head CT scan is a rapid and valuable imaging modality for evaluating the extent of hydrocephalus in sarcoidosis, as it can demonstrate ventricular system dilatation (A). Granulomatous inflammation can impair CSF reabsorption at the arachnoid villi or obstruct CSF flow. Brain MRI (T1W sequences) with gadolinium enhancement in panels B (axial) and C (coronal) disclose focal areas of enhancing lesions obstructing the CSF flow through the foramina of Monro (arrows), leading to hydrocephalus.

Seizures and status epilepticus.

Seizures are a common neurological complication of neurosarcoidosis, frequently produced by parenchymal granulomatous lesions and/or meningeal involvement (Figure 3). Prompt recognition is essential, with immediate initiation of benzodiazepine followed by anti-epileptic drugs such as levetiracetam, valproate, or phenytoin.⁸¹ Head CT scan and/or brain MRI should be performed urgently to assess for brain lesions, particularly active inflammatory lesions, and to determine the need for early initiation of steroid and/or immunosuppressive therapy in patients with a new diagnosis of sarcoidosis or escalation of treatment in patients with known disease already on treatment.⁸⁴ In some patients, granulomatous lesions may involve the brainstem or cranial nerve nuclei, which may directly impair consciousness and disrupt respiratory control. In such cases, as well as in those with status epilepticus or difficult-to-control seizures that require multiple antiseizure medications during the acute stage, airway protection, mechanical ventilation, and high-dose corticosteroids should be initiated. Depending on clinical severity, escalation to additional immunosuppressive therapy such as TNF inhibitors (e.g., infliximab) may be required during the intensive care unit stay.⁸⁵

Figure 3. Encephalitic and Hypothalamic Forms of Neurosarcoidosis.

Encephalitic forms of neurosarcoidosis can emerge acutely or subacutely and may be associated with neurological emergencies, including seizures, status epilepticus, or acute neuroendocrine syndromes. Figures A and B show a brain MRI (axial view) from a patient who presented with acute mental status and was found in status epilepticus. Panel A (MRI FLAIR) discloses the extent of signal abnormalities within the frontal white matter bilaterally. Encephalitic lesions are frequently associated with meningeal forms, as shown in panel B, in which there is evidence of leptomeningeal enhancement, very prominent in the frontal lobes (T1W MRI + Gadolinium).

The hypothalamic form of neurosarcoidosis is a subtype of encephalitic form that occasionally presents acutely with neuroendocrine manifestations, including hypothermia, dysautonomia, and/or panhypopituitarism. Such neurological manifestations are associated with focal granulomatous inflammation that selectively affects the hypothalamic (panel C, coronal view, arrow) and/or pituitary gland structures (panel D, sagittal view, arrow) (T1W MRI + Gadolinium).

Cerebrovascular disease.

Cerebrovascular involvement in neurosarcoidosis may present acutely with motor weakness, sensory disturbances, visual deficits, and cognitive or behavioral changes.^45,86,87 Many patients with systemic sarcoidosis or neurosarcoidosis also have traditional risk factors for cerebrovascular disease, including cardiomyopathies, diabetes, hyperlipidemia, and obesity, which may complicate the diagnostic process.⁸⁸ In neurosarcoidosis, cerebrovascular disease may result from cerebral vasculitis driven by perivascular granulomas, which lead to vessel wall thickening, luminal narrowing, and ultimately ischemic or hemorrhagic strokes (Figure 4).^44,86,87,89 Clinicians should therefore distinguish between cerebrovascular events caused by conventional vascular risk factors and those resulting from granulomatous inflammation of the CNS, as the treatment approach is different: strokes resulting from inflammatory vasculopathic changes may require aggressive anti-inflammatory control rather than the standard stroke management. These inflammatory vascular manifestations may be more common than previously recognized and merit routine evaluation. Brain MRI and magnetic resonance angiography (MRA) are the primary imaging modalities used to assess cerebrovascular involvement. Typical findings include perivascular enhancement, ischemic lesions, and hemorrhagic changes (Figure 4). Advanced techniques such as MRI vessel wall imaging and digital subtraction angiography (DSA) are particularly valuable for detecting vascular inflammation, revealing vessel wall thickening and contrast enhancement, which are characteristic of cerebral vasculitis^76,90,91

Figure 4. Stroke as an emergency in neurosarcoidosis.

Acute onset of cerebrovascular disease is a rare but challenging complication in the context of neurosarcoidosis. Panels A and B show a contrast-enhanced head CT scan (A) and brain perfusion CT images of a young man with a prior history of sarcoidosis who was admitted with sudden mental status changes. Panel A reveals focal low-density areas in the frontal lobes and deep gray nuclei (arrows). The CT perfusion scan (B) displays significant focal hypoperfusion in the frontal lobes, more prominent on the right, as well as in the deep gray matter structures (heat map showing purple and blue for major hypoperfusion, yellow and red for higher perfusion). Brain MRI shows corresponding signal abnormalities bilaterally in the frontal and deep gray nuclei, consistent with ischemic injury (arrows, panel C, FLAIR sequence). MRI with contrast (T1W MRI + Gadolinium) reveals selective bilateral enhancement of the Sylvian fissures and perimesencephalic structures (arrows, panel D). The granulomatous inflammation in these areas likely caused significant narrowing of the distal internal carotid arteries and segments M1 and M2 of the middle cerebral arteries (arrows, panel D), leading to the strokes shown in panel C.

Neuroendocrine dysfunction.

Occasionally, pituitary-hypothalamic dysfunction is an overlooked complication of neurosarcoidosis that needs special attention. This typically occurs through hypothalamic or pituitary gland granulomatous infiltration, leading to central diabetes insipidus or hypogonadism (Figure 3).^42,74,75 Rarely, such conditions lead to critical illness, but clinicians should be aware that neurosarcoidosis patients with neuroendocrine involvement are at risk of acute adrenal crisis, in which hypotension, altered mental status, and hypoglycemia may require ICU care for immediate IV steroids and supportive treatment. Patients may need electrolyte and volume management, initiation of desmopressin, and stress-dose hydrocortisone.^92,93 Occasionally, patients with sarcoidosis and hypothalamic involvement may present with acute bradycardia, hypothermia, and sleep disturbances.⁷⁴

COMPLICATIONS OF IMMUNOSUPPRESSIVE THERAPY IN CRITICAL CARE

High-dose corticosteroids are often the first-line agents, followed by cytotoxic or biologic immunosuppressive agents for refractory or severe disease. These treatments are known to carry substantial risks for severe infections, metabolic derangements, and organ-specific toxicities, especially in ICU settings.⁹⁴

Opportunistic infections and risk of infection reactivation.

Although uncommon, opportunistic infections (OIs) can occur in sarcoidosis or neurosarcoidosis due to prolonged use of glucocorticoids, immunosuppressants, or biological agents, including TNF and IL-6 inhibitors.^95,96 OIs should be treated as medical emergencies, as their occurrence often requires reevaluation of the established treatment, potential discontinuation or modification of immunosuppressive therapy, and initiation of antimicrobial treatment. These situations can introduce additional complications and comorbidities in patients who are already immunosuppressed. Common OIs include cryptococcosis, aspergillosis, and tuberculosis.⁹⁷ Importantly, clinicians should remain vigilant for fungal infections that can mimic sarcoidosis, such as histoplasmosis, cryptococcosis, and blastomycosis, as such diseases may be misdiagnosed as sarcoidosis. Initiating immunosuppressive therapies may worsen such infections. Progressive multifocal leukoencephalitis (PML), a subacute-chronic encephalitic disorder produced by the reactivation of JC virus, can occur in patients with sarcoidosis, either as a disease-associated complication or as a result of long-term immunosuppression.^95,98,99

Steroid-induced hyperglycemia.

A high risk of diabetic ketoacidosis or hyperosmolar hyperglycemic complications is present in patients with IV methylprednisolone or prolonged oral prednisone use, particularly among those with pre-existing diabetes mellitus.^100,101 Close metabolic monitoring and strict glucose control, often requiring intravenous insulin protocols and careful electrolyte management, are essential in these patients.^92,93 In addition, high-dose corticosteroids increase the risk of stress ulcers and subsequent gastrointestinal bleeding or perforation. Therefore, stress ulcer prophylaxis with a proton pump inhibitor or H2 blocker should be implemented during high-dose steroid therapy^{101 102}.

Adrenal crisis.

Secondary and tertiary adrenal insufficiency can present acutely in patients with sarcoidosis and neurosarcoidosis, especially in critically ill individuals receiving prolonged corticosteroid therapy or those with pituitary or hypothalamic neuroinflammatory involvement. These forms of adrenal insufficiency result from suppression of the hypothalamic-pituitary-adrenal axis. Clinically, patients may develop rapidly progressive severe fatigue or weakness, altered mental status, tachycardia, and severe hypotension. Electrolyte abnormalities, including hyponatremia and hyperkalemia, are common.¹⁰³ If left untreated, these complications carry a significant risk of mortality. Prompt administration of stress-dose intravenous hydrocortisone is essential, followed by a gradual taper as the patient stabilizes¹⁰⁴.

Bone marrow suppression and cytopenias.

Marked lymphopenia, which may involve both T-cell populations, CD4+ and CD8+ as well as B cells, may occur in sarcoidosis and it is associated with disease severity and increased inflammatory activity.^105–108 Long-term immunosuppressant and cytotoxic agents used in sarcoidosis and neurosarcoidosis, such as methotrexate, mycophenolate mofetil, azathioprine, and cyclophosphamide, are also associated with the development of cytopenias and other immunological disturbances. These side effects may increase the risk of complications such as severe infections, sepsis, septic shock, and potentially death.¹⁰⁶ Regular monitoring, including complete blood count with differential, is recommended. Recent studies suggest that a high neutrophil-to-lymphocyte ratio in sarcoidosis may have prognostic value, as it is associated with disease progression.¹⁰⁹ Modification of immunosuppressive agents may be necessary if these agents are believed to contribute to cytopenias.

MANAGEMENT AND THERAPEUTIC APPROACHES IN NEUROSARCOIDOSIS

The management of the neurological complications in neurosarcoidosis requires a multidisciplinary approach that addresses not only the neurological manifestations but also the systemic features of sarcoidosis and its frequently associated comorbidities, such as diabetes and cardiovascular disorders, including cardiomyopathies.^3,6,110 In the acute or subacute phases, treatment focuses on reducing the severity of granulomatous inflammation. Corticosteroids remain the first-line treatment for both systemic and neurological manifestations during the acute and subacute phases. At the same time, early introduction of steroid-sparing medications as the drugs of choice for long-term management is recommended when sustained control of granulomatous inflammation in the CNS or other affected organs is necessary (Table 3).^{85,94,111–113} However, the introduction of high-efficacy medications, such as TNF inhibitors and new drugs that target specific immune mechanisms, including the IL-6 and JAK-STAT pathways, is becoming an increasingly attractive option for managing aggressive or refractory cases of complicated sarcoidosis and neurosarcoidosis in the critical care setting.^114–116

Table 3.

COMMON TREATMENG DRUGS USED IN NEUROSARCOIDOSIS

Therapy Class	Onset of Action1	Dosing/Frequency2	CNS Bio-availability3 & Clinical use	Adverse effects	Refs
Glucocorticoids
Methyl prednisolone	Hours (IV)	500–1000 mg daily, IV, 3–5 days during acute stages or emergencies	High (IV) CBA Acute/ Long-term use.	Hyperglycemia, psychosis, depression, infection, gastritis, osteonecrosis, osteoporosis	1–3
Prednisone	Days (PO)	0.3–1mg/kg daily, PO, Variable dosing based on disease acuity, stage	Good (PO) CBA Acute/Long-term use. Taper to lowest effective dose; first-line	Same as above, dose-dependent, adrenal crisis if stopped abruptly after prolonged use	1–3
Dexamethasone	Hours (IV), days (PO)	0.75–9mg/day PO/IV	High CBA Acute use Used in CNS edema, alternative to other steroids	Same as above, more potent, longer half-life	4
Conventional Immunosupressors
Methotrexate	ECE 4–8 weeks, FTE 8–16 weeks	10–25mg weekly, PO or SC, Oral to SC conversion is 1:1	Moderate CBA Long-term use Combine with folic acid;	Hepatotoxicity, cytopenias, GI side effects, pulmonary toxicity, folate deficiency	3,5,6
Mycophenolate mofetil	ECE 4–8 weeks. FTE 12–24 weeks	1000–1500 twice a day, PO	Moderate CBA Long-term use	GI intolerance, cytopenias, infection	3,6,7
Azathioprine	ECE 6–8 weeks. FTE 12–24 weeks	1–2mg/kg/day, PO	Moderate CBA Long-term use	Leukopenia, bone marrow suppression, hepatotoxicity, infection, pancreatitis and GI effects	3,7
Targeted Immunomodulators
Infliximab (TNF inhibition)	ECE 2–4 weeks, FTE 6–12 weeks	5–10mg/kg IV at 0, 2, 6 weeks then q4-8 weeks	Good CBA Acute/Long-term use Useful in severe neurosarcoidosis and during acute/critical care Potential ADA development	Infusion reactions, anaphylaxis, infection, TB reactivation, malignancy	5,8–14
Adalimumab (TNF inhibition)	ECE 4–8 weeks, FTE 6–12 weeks	40mg weekly, SC	Good CBA Long-term use Alternative to infliximab Potential ADA development	Injection site reactions, infection, TB reactivation, malignancy	3,15–17
Tocilizumab (IL-6 inhibition)	ECE 1–2 weeks, FTE 6–12 weeks	8mg/kg IV q4wks or 162mg SC q1-2wks	Moderate CBA Acute/Long-term Limited data in Neurosarcoidosis	Infection, neutropenia, elevated LFTs, GI perforation	18–20
Rituximab (B-cell depletion)	ECE 4–8 weeks. FTE 12–24 weeks	375mg/m2 IV q1wk × 4 or 1g IV q2wks × 2, then q6-12mo	Moderate CBA Long-term Limited data in neurosarcoidosis	Infusion reactions, infection, hypogammaglobulinemia, PML	21
New Promising Treatments 4
Tofacitinib (JAK inhibition)	ECE 2–6 weeks. FTE 8–12 weeks	5mg twice a day, PO	Unclear CBA Long-term Promising in cutaneous and systemic sarcoidosis	Infection, cytopenias, lipid elevation, VTE, malignancy	22–25
Ruxolitinib (JAK inhibition)	ECE 2–4 weeks. FTE 8–12 weeks	5–20mg twice a day, PO	Unclear CBA Long-term Preclinical/early data only	Infection, cytopenias, elevated LFTs, VTE, malignancy	26 24

¹Onset of action is based on the literature available for rheumatological disorders or other neuroinflammatory disorders in which the medication has been used, as there is no specific data for neurosarcoidosis.

²Based on recommendations given for systemic sarcoidosis^1–3 or observational studies in neurosarcoidosis (given in the reference column).

³For neurosarcoidosis treatment, CNS bioavailability in brain inflammation does not depend solely on the permeability of the normal BBB to the drug, but also on the crossing of the drug through a disrupted BBB due to neuroinflammation.

⁴Limited data in neurosarcoidosis

Abbreviations: CBA: CNS bioavailability; ECE: Early clinical effect; FTE: Full therapeutic effect; PO: oral administration; IV: intravenous administration; SC: subcutaneous administration; ADA: anti-drug antibody; GI: gastrointestinal; TB: tuberculosis; PML: Progressive multifocal leukoencephalopathy; LFT: Liver function test; VTE: venous thromboembolism; JAK: Janus kinase.

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A Consensus Recommendation to address the challenges associated with the management of neurosarcoidosis was recently published to provide expert-derived guidelines⁸⁵. Due to limited randomized controlled trials for neurosarcoidosis, the recommendations were developed through a Delphi survey to achieve consensus among specialists and reach agreement on five key topics. First, treatment should be individualized based on the neurosarcoidosis phenotype and disease severity; a uniform stepwise escalation strategy is not recommended for all cases. Second, glucocorticoids are recommended as part of the initial treatment for all phenotypes. In severe cases, the early use of high-efficacy agents, such as TNF inhibitors, is advised. Third, maintenance of targeted immunomodulation with agents such as infliximab or adalimumab is recommended for at least 1 year, regardless of the initial treatment response, for moderate-to-severe disease. Fourth, follow-up imaging should be performed within 2–6 months of initiating therapy if baseline imaging was abnormal. Regular clinical assessments, along with gadolinium-enhanced MRI scans, are recommended to monitor treatment response and disease progression. Finally, cautious tapering of glucocorticoids is recommended within the first year, once clinical stability has been achieved, to avoid the cumulative adverse effects of such medications and worsening of comorbidities such as diabetes. However, there was a lack of consensus on the optimal dosing and duration of specific immunosuppressive agents, treatment approaches for PNS involvement, standardization of glucocorticoid dosing across phenotypes, and strategies to reduce the risk of anti-drug antibody formation with TNF inhibitors.

Glucocorticoids.

Glucocorticoids are considered the first-line treatment for sarcoidosis and neurosarcoidosis, particularly during the acute and subacute phases or in cases of suspected neurosarcoidosis with active neuroinflammatory symptoms, even when the diagnosis is not yet confirmed.⁸⁵ Due to their lipophilic properties, glucocorticoids readily cross cellular membranes, including the blood–brain barrier (BBB), allowing them to exert both rapid non-genomic effects (within minutes) and genomic effects (within hours to days). Their genomic actions include upregulating anti-inflammatory proteins and downregulating pro-inflammatory cytokines (e.g., IL-6, IL-12, TNF-α, and IFN-γ), chemokines, and adhesion molecules, thereby promptly suppressing acute inflammation. High-dose intravenous methylprednisolone is the preferred option in acute neuroinflammatory presentations, particularly in critically ill patients or those with rapidly progressing symptoms. In less severe cases, where inpatient care is not required, high doses of oral prednisone or methylprednisolone can be effective for managing acute manifestations in the outpatient setting.^111,112 The duration of IV treatment, transition to oral corticosteroids, and the maintenance and tapering schedule should be carefully individualized based on the patient’s neurosarcoidosis phenotype, disease severity, and clinical response. Recently, the use of glucocorticoids in combination with TNF inhibitors to facilitate disease control and reduce long-term steroid use was recommended for the treatment of acute neurological situations that require critical care management.⁸⁵ The introduction of steroid-sparing agents or other immunosuppressive therapies is often initiated during the acute or subacute phases, in conjunction with corticosteroid treatment, to facilitate a timely transition to long-term maintenance strategies and minimize cumulative glucocorticoid toxicity.^3,4,117,118

Conventional immunosuppressors.

Antimetabolite immunosuppressive agents such as methotrexate, mycophenolate mofetil, and azathioprine have been traditionally used as steroid-sparing therapies for the long-term management of sarcoidosis and its complications, including neurosarcoidosis. Their effectiveness has been supported by retrospective case series and observational studies, although no randomized controlled trials have confirmed their efficacy in this setting.^{73,84,119–122} One of the main limitations of these agents in neurosarcoidosis is their limited CNS penetration and delayed onset of immunosuppressive effect. Clinical effects often take weeks to months, which limits its utility in acute, rapidly progressive disease. Their use in neurosarcoidosis is primarily based on their indirect immunosuppressive effect, which broadly suppresses T and B cell activity and modulates immune cell trafficking into the CNS, thereby reducing systemic immune-mediated CNS inflammation. Because of this delay, these medications are not suitable for managing acute complications of sarcoidosis, neurosarcoidosis, or for use in the critical care setting. In such scenarios, high doses of IV or oral glucocorticoids are typically required as first-line therapy and may need to be continued for prolonged periods until more targeted immunomodulators, such as TNF inhibitors, achieve a clinically meaningful immunological effect and stabilize the neuroinflammation associated with the disease manifestations.⁸⁵ Although other immunosuppressants, such as cyclophosphamide, offer a faster onset of immune effect, often within 1 to 2 weeks when administered intravenously at high doses, their use in neurosarcoidosis is limited due to their broad cytotoxic effects.¹²³ These include risks for gonadal toxicity leading to infertility, hemorrhagic cystitis, or severe leukopenia that increases the risk of infections. Additionally, in patients with systemic sarcoidosis, cyclophosphamide may exacerbate involvement of vulnerable organs such as the heart and increase the risk of cardiomyopathy.³⁹ However, in the acute and subacute phases of the disease, particularly in critical care settings, cyclophosphamide may be considered a treatment of last resort for severe or refractory neuroinflammation, especially in the encephalitic or myelitic phenotypes of neurosarcoidosis.¹²³ This is followed by a transition to safer maintenance immunosuppressive therapies once stabilization is achieved. When conventional immunosuppressants are used in the long-term management of sarcoidosis and neurosarcoidosis, careful monitoring is necessary due to potential adverse effects, including myelosuppression, cytopenias, liver dysfunction, and increased susceptibility to infections.¹¹⁹

Targeted immunomodulators.

Immunomodulatory medications modulate the activity of specific immune pathways by enhancing or inhibiting them, thereby modifying the immune response and limiting immune-mediated injury rather than broad immunosuppression. Although several immunomodulators and biological agents have been tested in pulmonary sarcoidosis¹²⁴, the understanding of their therapeutic role in the management of neurosarcoidosis remains very limited.¹²⁵ Three major groups of immunomodulatory medications are used in sarcoidosis: TNF inhibitors, IL-6 inhibitors, and B-cell depleting therapies.

TNF inhibitors.

Anti-TNF agents are potent immunomodulatory therapies that inhibit tumor TNF-α, a pro-inflammatory cytokine produced primarily by macrophages and T cells. TNF-α plays a central role in neuroinflammatory disorders and in the granulomatous inflammation characteristic of sarcoidosis, including neurosarcoidosis.¹²⁶ The monoclonal antibodies infliximab and adalimumab are the most widely used TNF inhibitors in this context as they have demonstrated substantial efficacy in acute and rapidly progressive presentations of neurosarcoidosis.^{127 122,124,125,128–133} Although their large molecular size limits CNS penetration under normal conditions, their effectiveness is likely due to a combination of a disrupted BBB in active disease, allowing limited but clinically meaningful CNS access and peripheral immunomodulation, including rapid suppression of systemic inflammation and reduced trafficking of activated immune cells into the CNS. Although no randomized controlled trials have evaluated the efficacy of Infliximab in neurosarcoidosis, retrospective and observational studies support its efficacy,^{118,120,125,129,130,132–134} including the use of infliximab biosimilars.¹³⁵ Due to its intravenous administration, rapid onset of immunological action (3–7 days), and sustained effect (2–6 weeks), infliximab is a highly effective therapy to manage acute and critical neurological complications, often in combination with glucocorticoids, until disease control is achieved.¹³⁶ However, infliximab use has limitations. One major concern is the risk of heart failure exacerbation, which is particularly relevant in patients with cardiac sarcoidosis.¹³⁷ In addition, screening for latent tuberculosis, hepatitis, fungal infections, and a personal or family history of demyelinating disorders, such as multiple sclerosis, is essential before initiation of treatment, as TNF inhibitors have been associated with the reactivation of infections and, rarely, demyelinating disease.¹²⁵ There is currently no consensus on the duration of treatment with TNF inhibitor treatment in neurosarcoidosis.⁸⁵ However, clinical experience suggests that infliximab, either alone or in combination with low-dose glucocorticoids or conventional immunosuppressants (e.g., methotrexate), can be effective for long-term management in selected patients.¹²⁵ A key challenge in the long-term use of infliximab is the potential development of anti-infliximab neutralizing antibodies, which can reduce the therapeutic effect. A therapeutic drug monitoring with scheduled assessment of drug levels and anti-drug antibodies is recommended.¹³⁸ To mitigate the development of anti-drug antibodies, the concomitant use of methotrexate has become a common clinical practice, as it reduces immunogenicity and prolongs the treatment response¹³⁹. If neutralizing antibodies develop, switching to adalimumab or other immunomodulators is an alternative treatment strategy.

Interleukin-6 inhibitors.

The IL-6 signaling pathway plays a key role not only in systemic inflammation but also in immune regulation within the CNS.^140,141 Most of the treatment strategies primarily target the IL6 receptor, with agents like Tocilizumab and Sarilumab already used off-label in refractory sarcoidosis.^142,143 Studies of the immunopathogenesis of sarcoidosis and neurosarcoidosis highlight the critical involvement of IL-6-mediated pathways,¹⁶ suggesting that drugs such as Tocilizumab and newer agents like Satralizumab, currently approved for NMO, may be promising options for treating acute or refractory neurosarcoidosis. Although experience with IL-6 receptor inhibitors in neurosarcoidosis is limited, growing clinical evidence supports their effectiveness in other neuroinflammatory disorders resistant to conventional immunosuppressive therapies.^144–146 However, as with other immunomodulatory therapies, IL-6 inhibitors carry an increased risk of infections, including the reactivation of latent infections, and should be used cautiously in patients with a high risk of malignancy.

B-cell depleting agents.

Although B-cell-depleting therapies were initially developed to target antibody production in autoimmune diseases such as systemic lupus erythematosus and later used in neuroinflammatory disorders, including NMO, multiple sclerosis, and autoimmune encephalitis,¹⁴⁷ there is growing interest in their use for sarcoidosis.¹⁴⁸ These therapies target surface proteins, specifically CD19 and CD20, which are essential for B-cell functions, including proliferation, differentiation, antigen processing, and cytokine production. In sarcoidosis, granulomatous inflammation often includes B-cell infiltration and elevated levels of B-cell-associated cytokines, providing a biological rationale for the use of B-cell-depleting agents. Rituximab, a humanized monoclonal anti-CD20 antibody, is already widely used in the management of neuroinflammatory diseases¹⁴⁹ and has shown a potential benefit in a small series of cases of sarcoidosis.^124,150 The use of Rituximab in neurosarcoidosis has been limited, and few studies have shown mixed results.¹⁵¹ Although B-cell depletion may have a potential therapeutic effect for neurosarcoidosis refractory to conventional immunosuppression or TNF inhibitors, its use in the acute critical care of neurosarcoidosis complications may be limited by its delayed onset of clinical action, typically requiring 4 to 12 weeks to achieve a significant effect, and may only be beneficial for the long-term management.¹⁵² Emerging therapies targeting CD19, such as inebilizumab, already approved therapy for NMO,¹⁵³ may offer broader B-cell depletion, affecting earlier stages of B-cell development and plasmablasts. However, there is no report of its use in sarcoidosis or neurosarcoidosis. Like other immunomodulatory therapies, concerns about infection risk, neutropenia, and hypogammaglobulinemia may limit their long-term use.¹⁵⁴

Assessment of the risk of reactivation of infection.

A critical part of the management of neurosarcoidosis is the evaluation of the risk of reactivation of infections such as tuberculosis, hepatitis B and C, and others in patients in whom treatments such as TNF inhibitors (e.g., infliximab or adalimumab), IL-6 modulators (e.g., Tocilizumab) or B-cell depleting therapies are being considered, or during regular monitoring of patients already on treatment. Interferon-gamma release assays, such as QuantiFERON Gold or T-SPOT tests, are the most reliable blood tests for TB surveillance or documentation of exposure.¹⁵⁵ Similarly, assessment of hepatitis B surface antigen (HBsAg) and anti-hepatitis B core (HBc) IgM antibody is a good indicator of acute infection or reactivation. However, nucleic acid amplification tests are the most specific assays for assessing acute or reactivation of hepatitis B or C, and should be used for regular infection surveillance.¹⁵⁶ Additionally, latent TB or HBV must be treated before considering any of the immunomodulatory agents.^157,158 Compared with other disorders in which immunosuppression exposes patients to Pneumocystis jirovecii pneumonia (PJP)¹⁵⁹, the frequency of this OI in sarcoidosis has not been well established. Prophylactic PJP treatment is generally considered for patients receiving high-dose corticosteroids and/or combination immunosuppressive therapies.¹⁶⁰ In our practice, we empirically offer PJP prophylaxis to patients receiving prednisone >= 15 mg daily who have lymphopenia (absolute lymphocyte count < 800) or are treated concomitantly with immunosuppressive agents. However, there are currently no formal guidelines specifically addressing PJP prophylaxis in sarcoidosis.

Potential promising drugs with limited information in neurosarcoidosis

Janus kinase (JAK) inhibitors.

Blocking JAK enzymes to modulate cytokine and growth factor signaling has emerged as a promising strategy to suppress inflammation and modulate immune responses. JAK inhibitors target key cytokines such as IL-6 and IFNγ, which are involved in granuloma formation, providing a rationale for their use in sarcoidosis.¹⁶¹ Small case series have reported the use of tofacitinib (a JAK1/JAK3 inhibitor) and ruxolitinib (a JAK1/JAK2 inhibitor) in patients with sarcoidosis, including cutaneous and neurosarcoidosis forms^116,124,162. However, in cases of acute or severe neurosarcoidosis, the use of JAK inhibitors may be limited due to their limited CNS penetration and relatively slow onset of action (typically 4 to 12 weeks). Despite these limitations, their systemic anti-inflammatory effects, oral administration, and the potential for enhanced CNS penetration during active neuroinflammation suggest that JAK inhibitors may have value in the long-term management of neuroinflammatory sarcoidosis that may be considered after failure of TNF- and IL-6 inhibitors.¹⁶³ As with other immunomodulators, monitoring for infection risk, cytopenias, and lipid elevation is needed to prevent coronary artery disease¹⁶².

SUMMARY:

Neurosarcoidosis is a rare but severe manifestation of sarcoidosis that can cause permanent neurologic disability. This review provides a practical guide for clinicians—including internists, pulmonologists, and critical care specialists on approaches to evaluate, diagnose, and manage patients with or without known systemic sarcoidosis. It highlights key acute syndromes such as seizures, stroke, hydrocephalus, myelopathy, and neuroendocrine complications, emphasizing the use of diagnostic tools, particularly in emergency and critical care settings.