Neurosarcoidosis: Inflammation, Damage, and Treatment response

Research output: ThesisPh.D. thesis

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Abstract

This Ph.D. relates to neurosarcoidosis, a rare manifestation of the disease sarcoidosis,where the central nervous system is affected. Sarcoidosis is characterized by nonnecrotizing granulomatous inflammation. Although all organs can be affected bysarcoidosis, it most frequently occurs in the lungs and lymph nodes. In neurosarcoidosis,there is a great risk of permanent injury.

This Ph.D. study aimed to examine a cohort of patients with neurosarcoidosis for the type of central nervous system (CNS) inflammation, level of nerve damage, and clinical course after one year of treatment with standard immunosuppression.

From January 2016 to August 2020, we prospectively included all patients with possible connective tissue disease in the CNS, including neurosarcoidosis, from the Department of Neurology and Rheumatology, Odense University Hospital. In total, we included 20 neurosarcoidosis patients who met the criteria for “Highly probable neurosarcoidosis” according to the 2014 World Association of Sarcoidosis and Other Granulomatous Disorders definition.

In paper I, “Inflammatory profiles in plasma and cerebrospinal fluid of patients with neurosarcoidosis” (PMID: 35366560), we compared the cerebrospinal fluid (CSF) and plasma of neurosarcoidosis patients with those of healthy controls. The study showed significant inflammation. Twenty-five out of 38 inflammatory biomarkers were significantly elevated in CSF, and 12 inflammatory markers were significantly elevated in plasma. The inflammatory profile was a typical sarcoidosis Th1 inflammation profile with macrophage activity. Upregulation of chemokines and soluble adhesion molecules in CSF indicated active recruitment of monocytes, macrophages, CD4+ and CD8+ cells to the CNS across the blood-brain barrier.

In paper II, “Elevated neurofilament light chain in cerebrospinal fluid and plasma reflect inflammatory MRI activity in neurosarcoidosis” (PMID: 33672795), we measured the protein neurofilament light chain (NFL) concentration. NFL is a skeletal protein that is specific to nerve cells. If the axonal membrane of the nerve cells is damaged or destroyed, NFL leaks via the extracellular space to the CSF and subsequent plasma. In
neurosarcoidosis patients, the NFL was elevated 6-fold in CSF and 4-fold in plasma compared to sarcoidosis patients without CNS involvement and healthy controls as an indication of significant nerve damage. Furthermore, the nerve damage was dependent on
the extent of the inflammation on the MRI scans of neurosarcoidosis patients.

In paper III, “A prospective, one-year follow-up study of patients newly diagnosed with neurosarcoidosis” (PMID: 35717739), the 20 neurosarcoidosis patients were followed prospectively for 12 months. The immunosuppression was well-tolerated by patients and there were no significant side effects. During treatment, NS patients showed significant improvements in their MRI scans of the CNS, daily functioning, cognitive ability, and health perception of the disease. Despite these positive treatment results, the general functioning of neurosarcoidosis patients was still reduced after 12 months compared to that of the average population. The proportion of patients with significant fatigue and depression was also unchanged.

The results of this Ph.D. dissertation contribute to new knowledge about neurosarcoidosis in a patient group that has only been sparsely studied due to the rarity of the disease. The inflammation in neurosarcoidosis patients behaves like that of sarcoidosis patients who have inflammation of other organs. There appears to be active recruitment of inflammatory cells across the blood-brain barrier. The inflammation causes nerve damage, which correlates to the extent of inflammation shown on the MRI scans of the CNS. Immunosuppression is a well-tolerated and effective treatment for neurosarcoidosis patients, but they still have reduced functional capacity after one year.

Neurosarcoidosis patients are usually treated with immunosuppression for several years. In that context, 12 months is a short time. Future studies are needed to determine the
optimal length of treatment and to clarify whether intensified immunosuppression will improve the course of the disease. Likewise, longitudinal studies of the inflammatory markers and NFL could help predict patient outcomes, thereby targeting treatment by identifying the patients who have the greatest risk of permanent injury.

Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Ellingsen, Torkell, Principal supervisor
  • Nielsen, Helle Hvilsted, Co-supervisor
Publisher
DOIs
Publication statusPublished - 30. Sep 2022

Keywords

  • Neurosarcoidosis
  • Cytokine
  • Neurofilament light chain
  • Treatment

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