Sarcoidosis is a noncaseating granulomatous disease that causes inflammation and tissue damage in the involved organs. Although the etiology of the disease has not yet been elucidated, it is believed to be an immune-mediated disorder triggered by environmental factors.1 According to global estimates, the annual incidence of sarcoidosis is 5 to 40 cases per 100,000 people.2
The disease most commonly affects adults younger than 50 and prevalence rates are higher in women compared with men.2 Rates in the United States are more than 3 times higher in blacks than whites, with an adjusted annual incidence of 35.5 vs 10.9 cases, respectively, per 100,000 people.3
While the lungs and mediastinal lymph nodes are involved in more than 90% of patients with sarcoidosis, any organ may be affected.3 Nervous system involvement has been reported in 4% to 9% of patients.1 The clinical manifestations of neurosarcoidosis (NS) “are heterogeneous, as granulomatous inflammation may affect any anatomic substrate pertaining to the meninges, cranial nerves, brain, spinal cord, and peripheral nerves associated with diverse clinical forms of the disease,” wrote the authors of new diagnostic criteria for the disease.4
The abnormalities observed in NS may also be found in many other neurologic disorders, rendering diagnosis challenging, and the lack of laboratory measures specific to the disease further complicates diagnosis. Recognizing the need for diagnostic guidelines, the Neurosarcoidosis Consortium Consensus Committee (comprised of 10 neurologists and 4 pulmonologists) recently developed and published the consensus criteria for the diagnosis of NS based on a review of the literature and clinical experience.4 Key points of the criteria included:
- Because granulomas may also be caused by infectious diseases, malignant neoplasms, and a range of other disorders, it is critical that such causes be ruled out in patients with suspected NS. Cerebrospinal fluid (CSF) analysis can help confirm the presence of inflammation and rule out infectious or neoplastic causes. Between 50% to 70% of patients show nonspecific CSF markers of central nervous system (CNS) inflammation, including elevated protein, lymphocyte predominant pleocytosis, oligoclonal bands, and elevated immunoglobulin G (IgG) index.4
- Histologic tissue examination demonstrating noncaseating granuloma is the diagnostic gold standard for sarcoidosis. However, biopsy of neural tissue is rarely practical, so the Committee recommends a diagnostic approach that reflects the level of diagnostic certainty (possible, probable, or definite).
- In assessing patients with suspected NS, clinicians should thoroughly investigate systemic manifestations in addition to the neurologic examination. Evidence of systemic disease may not appear until later in the disease course. In a meta-analysis of 1088 patients with NS, systemic disease was evident upon presentation in only 31.1% of patients, although 84.0% of the sample ultimately developed systemic manifestations.5
- Nearly 90% of these patients show evidence of extraneural sarcoidosis, including in the lungs, skin, and joints.1 “Therefore, diagnostic strategies should focus on the evaluation of systemic disease in patients with an unknown history of sarcoidosis and neurologic disease suspected to be associated with sarcoidosis, as well as on staging the full extent of neurologic involvement to establish a definite or probably diagnosis of NS,” as stated in the guidelines.4
- A tissue biopsy of a nonneural site is recommended to definitively establish a diagnosis of multi-organ sarcoidosis. “The diagnosis of sarcoidosis is supported by the identification of granulomas in 1 or more organs…. [and] the biopsy results should be correlated with the clinical presentation for that particular organ.”
- Up to 90% of patients with sarcoidosis will demonstrate abnormalities on chest imaging.4 If chest x-ray results are normal in a patient in whom NS is highly suspected, the guidelines recommend performing a high-resolution computed tomography (CT) scan, ideally with contrast. If the CT scan results are normal, a gallium scan or fluorodeoxyglucose positron emission tomography (the latter is preferred) may help detect extrathoracic systemic sarcoidosis.
- In cases of suspected CNS sarcoidosis, magnetic resonance imaging (MRI) of the brain and/or cervical, thoracic, or lumbar spine should be conducted, as well as comprehensive CSF analysis. In cases of suspected peripheral nervous system (PNS) sarcoidosis, electromyogram (EMG) and a nerve conduction study (NCS) should be performed, along with nerve or muscle biopsy as clinically indicated.
- Each of the 3 proposed diagnostic categories (possible, probable, and definite) of NS includes the following prerequisite: “The clinical presentation and diagnostic evaluation suggest NS, as defined by the clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous inflammation of the nervous system and after rigorous exclusion of other causes.”
- In addition, in possible NS the criteria reflect that there is no pathologic confirmation of granulomatous disease, while in probable NS there is confirmation of systemic granulomatous disease consistent with sarcoidosis. In definite NS, nervous system pathology is consistent with NS, and there is also either evidence of extraneural sarcoidosis or no such evidence (isolated CNS sarcoidosis).
In summary, these 3 “categories of diagnostic certainty are proposed to emphasize the need for the clinician to maintain an open mind to alternate diagnoses on the basis of the patient’s clinical course and response to treatment,” the Committee concluded. “We anticipate that patients who meet the criteria for any of the diagnostic categories will be treated for NS,” although they suggest that only patients meeting the probable or definite criteria be included in future studies of the disease.
Neurology Advisor spoke with one of the Committee members, Carlos A. Pardo-Villamizar, MD, associate professor of neurology at Johns Hopkins University School of Medicine in Baltimore, Maryland, to further discuss the new guidelines and remaining needs pertaining to NS.
Neurology Advisor: What are some of the top diagnostic and treatment challenges in NS?
Dr Pardo-Villamizar: One of the main challenges in the diagnosis of NS is the limitation in obtaining brain or spinal cord tissue biopsies to confirm the diagnosis, as these may expose patients to risks. Having a clinical approach and diagnostic methodologies to achieve a more precise diagnosis in NS may help avoid difficulties in treatment. Unfortunately, most of the treatments for sarcoidosis are associated with adverse events and major cost.
For example, the most effective treatment for NS includes the chronic use of high doses of steroids, an approach that frequently may induce comorbidities and adverse effects. Other treatments are immunosuppressants, which are also associated with risk for opportunistic infections and adverse events and are extremely expensive. That means that improving diagnostic precision in NS may facilitate better management decisions in the right group of patients suspected of having NS.
Neurology Advisor: What will clinicians find helpful about the new guidelines?
Dr Pardo-Villamizar: The new recommendations outline the diagnostic strategies needed for determining a correct diagnosis of NS and establish a likelihood scale for a definite, probable, or possible diagnosis of the disease that would help define better management and treatment approaches. The guidelines, for example, emphasize the clinical spectrum and profile of different neurologic syndromes that may be associated with NS. Because most cases of NS are associated with systemic sarcoidosis, the new guidelines emphasize the need to establish a tissue diagnosis in non-neurologic organs to increase the likelihood of the diagnosis of central or peripheral nervous system involvement in the disease.
Neurology Advisor: What are some of the most pressing remaining needs in this area?
Dr Pardo-Villamizar: There is an urgent need for identification of better diagnostic biomarkers of the disease, either by brain and spinal cord imaging, or blood or CSF testing. Having new biomarkers of disease should minimize the misdiagnosis of NS in the setting of other neuroinflammatory diseases such as demyelinating disorders, myelitis, meningitis, or neurologic infections — disorders that frequently are confused with NS. In a similar fashion, there is an urgent need for developing new therapies that mitigate the development and chronicity of neuroinflammation associated with NS.
Neurology Advisor: How might these guidelines prove useful in addition to their clinical application?
Dr Pardo-Villamizar: The new guidelines will facilitate the design and development of clinical trials to test new therapies to minimize the burden of neurologic disability produced by NS.