Neurosarcoidosis: Contemporary Concepts in Classification, Neuroimmunopathogenesis, Neurophysiology, Diagnosis, and Management

Neurosarcoidosis is a rare but potentially disabling granulomatous neuroinflammatory disorder involving the central and peripheral nervous systems in patients with systemic or isolated sarcoidosis. Although clinically recognized in approximately 5–15% of patients with systemic sarcoidosis, subclinical neurological involvement may occur more frequently, suggesting significant underdiagnosis. Compared with the general population, patients with neurosarcoidosis experience markedly increased neuroimmune activation, chronic inflammation, neurological disability, cognitive dysfunction, psychiatric morbidity, autonomic instability, and reduced quality of life. The pathogenesis of neurosarcoidosis is multifactorial and involves genetic susceptibility, environmental triggers, dysregulated cellular immunity, cytokine-mediated inflammation, granuloma formation, blood-brain barrier dysfunction, oxidative stress, and progressive neurodegeneration. Activated CD4+ T-helper lymphocytes, macrophages, microglia, and inflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma play central roles in granulomatous neural injury. Granulomatous lesions may involve the meninges, cranial nerves, cerebral parenchyma, spinal cord, hypothalamic-pituitary axis, and peripheral nerves, resulting in highly heterogeneous clinical manifestations.

Clinically, neurosarcoidosis may present with cranial neuropathies, chronic meningitis, seizures, cognitive impairment, psychiatric disturbances, myelopathy, peripheral neuropathy, hypothalamic-pituitary dysfunction, autonomic instability, and chronic pain syndromes. Diagnosis remains challenging because no single biomarker or imaging modality demonstrates adequate sensitivity or specificity. Current diagnostic strategies rely upon integration of clinical findings, neuroimaging abnormalities, cerebrospinal fluid analysis, histopathological confirmation, and exclusion of infectious, autoimmune, neoplastic, and vascular mimics.

This descriptive review explores the contemporary understanding of neurosarcoidosis including epidemiology, classification, pathogenesis, neurophysiology, immunopathology, clinical manifestations, diagnosis, differential diagnosis, therapeutic strategies, prognosis, limitations, and future directions while emphasizing the profound neurological and systemic burden associated with this challenging neuroinflammatory disorder.