Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by non-caseating granulomas. The lungs, skin, and eyes are commonly affected organs, but when it involves the central nervous system (CNS) and/or peripheral nervous system (PNS), it is called neurosarcoidosis (NS). It may occur alongside sarcoidosis in other organs or affect the nervous system alone.
In Japan, sarcoidosis is relatively common and is the leading cause of uveitis. It peaks in men in their 20s, and in women shows a bimodal distribution with peaks in their 20s and 50s–60s.
Neurological involvement is observed in 5–15% of sarcoidosis patients4)7). Autopsy findings suggest that up to 25% may have neurosarcoidosis, indicating a possible high rate of subclinical cases. In approximately 70% of cases, neurological symptoms are the first sign of the disease3).
Symptoms of NS vary depending on the lesion site, ranging from a single symptom to complex multisystem manifestations.
General and Nonspecific Symptoms
Cranial nerve disorders
Neuro-ophthalmic symptoms
Meningitis symptoms
Spinal cord and peripheral nerve symptoms
Endocrine symptoms
Symptoms associated with vasculitis
Epileptic seizures
Key Findings of CNS Lesions
Diffuse leptomeningeal enhancement: The most frequent finding on gadolinium-enhanced MRI.
Cranial nerve enhancement: Contrast enhancement of cranial nerves including the facial and optic nerves.
Brain mass-like lesions: Single to multiple lesions. Easily mistaken for tumors or metastases.
Hydrocephalus: Both communicating and non-communicating types. Observed in 57% of cases 2).
Ocular Findings (6 items of IWOS criteria)
Granulomatous anterior uveitis: Mutton-fat keratic precipitates, iris nodules.
Angle nodules or tent-shaped peripheral anterior synechiae: Characteristic anterior segment findings.
Clump-like vitreous opacities: Snowball-like or bead-like opacities.
Retinal perivasculitis: Perivasculitis and nodules mainly occurring in veins.
Multiple waxy chorioretinal exudates: Or atrophic lesions resembling photocoagulation scars.
Optic disc granuloma or choroidal granuloma: Redness and swelling of the optic disc.
4 patterns on spinal MRI (PMC11213433)6)
Associated findings suggestive of ocular sarcoidosis: keratoconjunctivitis sicca, episcleritis/scleritis, lacrimal gland swelling, facial nerve palsy
Complications of ocular sarcoidosis: cystoid macular edema, epiretinal membrane, secondary glaucoma, complicated cataract
Characteristics of optic neuropathy: 28% develop bilaterally in a sequential manner, 37% have optic disc swelling, and 4% have perineuritis10).
Uveitis is the most common, and granulomatous anterior uveitis with mutton-fat keratic precipitates and iris nodules is characteristic. Ocular sarcoidosis is suspected when two or more of the six IWOS criteria (granulomatous anterior uveitis, angle nodules, snowball vitreous opacities, retinal perivasculitis, candlewax retinal exudates, and optic nerve head/choroidal granuloma) are present. In optic neuropathy, 28% of cases are bilateral 10).
The etiology of NS remains unknown. The basic pathology is non-caseating granuloma formation due to Th1 cell-mediated immune response (type IV allergy). It is hypothesized that prolonged exposure to antigenic stimuli leads to excessive activation of macrophages and T cells. In Japan, there are reports suggesting the involvement of Propionibacterium acnes.
The diagnosis of NS is made by integrating diverse clinical findings and test results. Although definitive diagnosis requires histological confirmation of non-caseating granulomas, CNS biopsy carries risks, so multiple diagnostic criteria are used.
| Certainty | Main Requirements |
|---|---|
| Definite | CNS biopsy shows non-caseating granuloma + clinical symptoms + exclusion of other diseases |
| Probable | Histological evidence of systemic sarcoidosis + laboratory findings of CNS inflammation |
| Possible | Clinical findings are suggestive but do not meet the above criteria |
Confirmation of non-caseating granulomas is the gold standard. CNS biopsy is ideal but highly invasive, so alternative sites such as lymph nodes, skin, conjunctiva, and transbronchial lung biopsy are considered.
Definitive diagnosis requires histological confirmation of non-caseating granulomas via CNS biopsy. However, due to its invasiveness, a stepwise diagnostic approach combining cerebrospinal fluid analysis (elevated protein, lymphocytosis), gadolinium-enhanced MRI, serum ACE and sIL-2R, and chest CT (to confirm BHL) is often used in practice. If non-caseating granulomas are confirmed in other sites (e.g., lymph nodes, skin, transbronchial lung biopsy), a probable diagnosis can be made.
Because this disease fluctuates in severity, mild cases may be observed with only steroid eye drops, expecting spontaneous remission. Severe cases require systemic steroid administration.
Anterior Uveitis
Posterior segment inflammation (severe cases)
An example of a prednisolone tapering regimen is shown below.
| Duration | Dose |
|---|---|
| 2 weeks | 30 mg/day |
| 1 month | 20 mg/day |
| 1 month | 15 mg/day |
| 1 month | 10 mg/day |
| 1 month | 7.5 mg/day |
| 1 month | 5 mg/day |
| 1 month | 5 mg every other day |
Treatment of ocular complications
First-line
Oral corticosteroids: First-line for mild to moderate cases.
Intravenous corticosteroids (pulse therapy): For severe or steroid-resistant cases. Methylprednisolone 1 g for 5 days, followed by oral prednisolone 1 mg/kg6).
Second-line
Methotrexate (MTX): The most frequently used immunosuppressant. It takes time to take effect, so it is used in combination with steroids.
Azathioprine and mycophenolate mofetil: Used as alternatives or additions to MTX.
Third-line
Infliximab: TNF-α inhibitor. Also used in cases with cerebral vasculitis.
Adalimumab: Also a TNF-α inhibitor. Increasingly used in refractory cases.
Cases with cerebral vasculitis: The combination of glucocorticoid + MTX/cyclophosphamide/infliximab is a major treatment strategy7). The hazard ratio for cerebrovascular events within 5 years after sarcoidosis diagnosis is markedly high at 10.067).
Epilepsy complication: Antiepileptic drugs such as levetiracetam are used concomitantly5).
Hormone replacement with hydrocortisone, levothyroxine, and desmopressin (for diabetes insipidus) is necessary for panhypopituitarism due to pituitary lesions. Nerve damage is often irreversible and may require lifelong replacement 4).
The treatment varies greatly depending on disease severity. In ocular sarcoidosis, prednisolone is typically tapered from 30 mg to 5 mg every other day over approximately 7 months. In severe or recurrent cases, a maintenance dose (5–10 mg/day) may be required long-term. Neurosarcoidosis often relapses and remits, making long-term follow-up essential.
Th1 cells release IL-2 and IFN-γ, recruiting and activating macrophages. Activated macrophages secrete cytokines, sustaining continuous granuloma formation. Histologically, epithelioid cells and multinucleated giant cells form the center, surrounded by lymphocytes, plasma cells, and mast cells. Asteroid bodies may be observed within multinucleated giant cells.
Granulomas form within or around the vessel wall, particularly in small penetrating arteries. The hazard ratio for cerebrovascular events within 5 years after sarcoidosis diagnosis is 10.06, indicating a markedly elevated risk of cerebrovascular complications 7).
Inflammatory myelin destruction is the main feature. Nerve and muscle biopsies reveal epineurial granulomas and endoneurial infiltration 6).
CSF flow obstruction due to granulomatous scarring of the meninges and impaired CSF absorption due to inflammation of the arachnoid villi occur. Both communicating and non-communicating types can occur2).
Granulomatous infiltration of the hypothalamus, pituitary stalk, and pituitary gland disrupts the endocrine axis. In severe cases, central diabetes insipidus with Na 168 (hypernatremia) may be present4).
MRI vessel wall imaging technology is expected to improve the diagnostic accuracy of vasculitis-related NS.
In a systematic review by Focke et al. (2025), MRI VWI successfully detected vessel wall lesions in 9 of 13 NS patients (69%)7). This technique may visualize vessel wall inflammation that is difficult to detect with conventional gadolinium-enhanced MRI.
Neopterin and lysozyme in CSF are attracting attention as biomarkers for vasculitis-associated neurosarcoidosis.
Focke et al. (2025) reported that CSF neopterin was elevated in 100% of cases (mean 5.2 ng/ml) and lysozyme in 75% (mean 4.25 mg/l) in patients with vasculitis-associated neurosarcoidosis7). These markers may serve as diagnostic tools.
As imaging alternatives to FDG-PET, somatostatin receptor imaging and PET imaging targeting CXCR4 (expressed on activated macrophages) are being explored.
JAK inhibitors such as tofacitinib and baricitinib are being explored for application in refractory sarcoidosis.
Some refractory NS cases have reported symptom improvement, but the role of rituximab in NS remains unclear at present6).
