Neurosarcoidosis is a rare inflammatory disorder that affects the central nervous system, including the brain, spinal cord, and peripheral nerves. This condition is characterized by the formation of granulomas, which are microscopic clumps of inflammatory cells, within the nervous system. Diagnosing neurosarcoidosis (NS) is often challenging because its symptoms, which can include facial weakness, headaches, and vision problems, closely resemble those of many other neurological diseases. The clinical process involves the step-by-step exclusion of other potential causes and the accumulation of evidence from various tests to confirm the diagnosis, requiring a multidisciplinary approach.
Initial Clinical Assessment
The diagnostic process begins with a detailed review of the patient’s medical history and a thorough neurological examination. Clinicians specifically look for any prior diagnosis of sarcoidosis in other organs, such as the lungs, skin, or lymph nodes. However, the nervous system can sometimes be the first or only part of the body affected, which complicates the initial assessment.
The neurological examination focuses on identifying non-specific signs of nervous system inflammation. One of the most common manifestations is cranial nerve palsy, which can present as sudden facial weakness or drooping. Patients may also report chronic headaches, sensory changes like numbness or tingling, and cognitive changes such as confusion or memory loss. This initial phase is crucial for raising suspicion of NS and differentiating it from more common neurological disorders.
Advanced Imaging Techniques
Magnetic Resonance Imaging (MRI) is the primary non-invasive tool for visualizing the nervous system and is a cornerstone in NS diagnosis. The MRI scan, particularly when enhanced with a contrast agent like gadolinium, can reveal patterns of inflammation highly suggestive of the disease. Characteristic findings include meningeal enhancement, which appears as thickening and brightening of the membranes surrounding the brain and spinal cord, often favoring the base of the brain.
The imaging may also show intraparenchymal lesions, which are areas of inflammation within the brain tissue itself, sometimes appearing as mass-like lesions. These lesions can also be found in the spinal cord and are often hyperintense on T2-weighted images. Involvement of specific structures like the optic nerve (resulting in nerve thickening and enhancement) or the hypothalamus and pituitary gland is also a highly suggestive finding.
Other imaging modalities, such as Positron Emission Tomography (PET) scans, play a supporting role in identifying systemic sarcoidosis outside the nervous system. A whole-body Fluorodeoxyglucose (FDG)-PET scan detects areas of increased metabolic activity, corresponding to inflammation, and can reveal occult disease in organs like the lymph nodes or lungs. Finding evidence of sarcoidosis elsewhere significantly strengthens the presumptive diagnosis of NS, often guiding the choice of a non-neural biopsy site.
Biochemical and Immunological Testing
Following imaging, a lumbar puncture is often performed to collect Cerebrospinal Fluid (CSF) for analysis, which provides direct evidence of inflammation within the central nervous system. In many patients with NS, the CSF analysis reveals a mild to moderate pleocytosis, meaning an elevated number of white blood cells, usually lymphocytes. Elevated protein levels in the CSF are also a common finding, often seen in about 60% of patients.
These CSF abnormalities, especially a combination of elevated protein and pleocytosis, support the diagnosis and help exclude infectious causes. Oligoclonal bands, which are markers of immune system activity within the CNS, are occasionally seen in NS, though they are far less common than in conditions like multiple sclerosis. The ratio of CD4 to CD8 T-cells in the CSF may also be elevated in NS.
Blood tests are conducted to look for markers of systemic sarcoidosis. Clinicians may check for elevated levels of the enzyme Angiotensin-Converting Enzyme (ACE), which is produced by the granulomas of sarcoidosis. While elevated serum ACE is found in up to 60% of systemic sarcoidosis cases, it is not consistently elevated in isolated NS and is not diagnostic on its own. Additionally, blood calcium levels are monitored, as sarcoidosis can sometimes lead to hypercalcemia, another indication of systemic disease.
The Role of Tissue Biopsy
The definitive diagnosis of any form of sarcoidosis relies on histopathological confirmation: the identification of noncaseating granulomas in affected tissue. These granulomas are microscopic collections of inflammatory cells without the central necrosis seen in some other diseases, such as tuberculosis. Obtaining a tissue sample is considered the gold standard for solidifying the diagnosis.
However, directly biopsying a lesion in the brain or spinal cord carries significant risks due to the delicate nature of the nervous system, so it is usually reserved for cases that are atypical or unresponsive to treatment. Because of this challenge, the diagnosis of NS is frequently presumptive, meaning it is made based on a combination of neurological symptoms, characteristic imaging findings, and evidence of sarcoidosis from a safer, non-neural site. The easiest sites to biopsy are often an enlarged lymph node, a skin lesion, or an area of avid uptake on a PET scan in the lungs.
If a biopsy from a systemic site confirms sarcoidosis and the patient presents with neurological symptoms consistent with NS, the diagnosis is considered “probable” or “definite,” depending on the consensus criteria. The process is ultimately an exercise in excluding other potential causes of granulomatous inflammation, such as infections or malignancies, before attributing the neurological findings to sarcoidosis.