Background

In neuroimmunology; biomarkers have been determined as having a pivotal role. Among them, Neurofilament Light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Interleukin-6 (IL-6), Osteopontin, Growth-associated protein 43 (GAP-43) have been examined for different central nervous system autoimmune disorders. It has been shown that each of them has a potential role for a different immunopathogenesis.

Objectives

In our study, we aimed to evaulate NfL, GFAP, Osteopontin, IL-6, GAP-43 in different subgroups of Multiple Sclerosis(MS). Relapsing-Remitting MS(RRMS)(n=38), Secondary-Progressive MS(SPMS)(n=16), Primary-Progressive MS(PPMS)(n=8), were included in this study. The samples from aquaporin-4(AQP4)-Ab-positive NMOSD(n=7), Myelin Oligodendrocyte Glycoprotein(MOG)-Ab-positive(n=9) patients and healthy controls(HC)(n=20) were also studied. All biomarkers were evaluated both in serum and cerebrospinal fluid (CSF).

Methods

Serum (n=98) and available CSF (n=20)(paired with serum,only MS subtypes) samples have used this cross-sectional study. For measuring NfL and GFAP concentrations in sera and CSF samples, we used SIMOA technology and assays on the Quanterix SIMOA HD-X ANALYZER. IL-6 measurements were performed on the Roche Cobas e-411 analyzer with the electrochemiluminescence method. Osteopontin and GAP-43 levels determined with the ELISA assays. Clinical and radiological data at sampling were collected for each case.

Results

We observed a significant positive correlation between serum NFL,GFAP and CSF NFL,GFAP levels in MS patiens(NfL,p=0,001,rho=0,686; GFAP,p=0,006,r_S=0,594). For serum samples, there was a very strong positive correlation between treatment-naive GFAP and treatment-naive NFL levels in MS patients (p<0,001, r_S=0,828). Additionaly, we have found negative correlation between serum IL-6 and GFAP levels in MS patients (p<0,01, r_S =-0,356). Also there was a negative correlation between serum IL-6 and NfL levels in MS patients (p<0,01, r_S =-0,422). When compared with HC, there was a significant incrase in terms of serum IL-6 levels in central neuroimmunological disorders(p<0,001).Mean value of AQP4-Ab-positive NMOSD serum GFAP levels(111,7±29,39 pg/mL) were signififantly higher than MOG-Ab-positive serum GFAP levels(80,39±32,53 pg/mL)(p<0,05). MOG-Ab-positive serum IL-6 mean values(42±52,17 pg/mL) were found to be higher than AQP4-Ab-positive NMOSD group(6,17±4,36 pg/mL)(p<0,05).

Conclusions

NfL and GFAP are certainly promising biomarkers in MS patients. NMOSD and MOG-Ab-positive patients have to be assessed in prospective studies that have a large number of patients. Our study is the first that Single Molecule Array (SIMOA) technology has been used in Turkey to evaluate NfL, GFAP levels both in serum and CSF levels.

Background

Fingolimod Rebound Syndrome (FRS) is defined as flare-up of the disease activity upon withdrawal of treatment in patients with MS. FRS is usually seen between the 4th and 16th week following fingolimod discontinuation. In different studies , FRS development rates change between 5% and 52%. It has been reported that, during cessation of fingolimod besides having low lymphocyte count and low EDSS score; response to the treatment (no clinical/radiological activity during the treatment period) and wash out period left after fingolimod could affect FRS development.

Objectives

The objective of this study was to identify our potential risk factors and the modifable determinants on the development of FRS.

Methods

MS patients presenting between 2012 – 2019 and treated with fingolimod were all included in the study. Fingolimod was discontinued after at least 6 months and those experience FRS after cessation were evaluated in terms of all demografic and treatment features.

Results

In totally 661 patients 8.9% (n=59) discontinued fingolimod depending on various reasons. Among the discontinued group 10 (16.9%) patients experienced FRS.

72.9% of the patients were female in the total discontinued group, 60% was female in the FRS group. The median (min-max) MS duration was 10 (2–25) years in the whole group, while it was 9 (4–23) in the FRS group. The median time under fingolimod was 42.5 (16–78) and 43.5 (13–72) months respectively in the discontinued and FRS groups. The washout period after fingolimod was statistically similar between groups (64.5 (7–1270) and 106.5 (7–1110) days respectively (p=0.117)). The mean±SD duration between drug discontinuation and development of FRS was found as 56.98±1.79 days. The median (min-max) of EDSS score of the FRS patients was 4 (1–7) and of the total group it was 4.5 (1–8.5).

Conclusions

Patients should be closely monitored during first two months of cessation of fingolimod therapy and appropriate immunomodulatory treatment should be initiated without delay.

Background

Neuromyelitis optica spectrum disorders (NMOSD) are a group of relapsing inflammatory autoimmune CNS diseases and as its known the coexistence of other autoimmune disorders such as Sjogren’s Syndrome is not rare. Here we report a patient whose initial diagnosis was NMOSD and Sjogren's Syndrome, but with immunosuppresive treatment she presented with anti-NMDAR encephalitis triggered by HSV Encephalitis.

Objectives

The most interesting point about this case is that it draws the attention to the coexistance of NMOSD and anti-NMDAR encephalitis. There are only 11 adult cases in the previous literature that have been reported anti-NMDAR encephalitis with NMOSD. Previous studies suggested that autologous immunity triggers AQP4 antibody releated cytotoxicity and meantime activation of NMDAR which end up with comorbidity. But the pathophysiology of this comorbidity has not been clearly established yet.

Methods

A unique case of NMOSD coexisting with Sjogren's Syndrome and anti-NMDAR encephalitis triggered by HSV encephalitis was reported.

Results

Our patient, who is a 52-year-old otherwise healthy female patient, applied to our clinic with paraparesis, and anesthesia under T2 level. Aqp-4 positive NMOSD was our initial diagnosis. In addition, her anti-Ro/SSA antibody was positive and salivatory gland biopsy showed Grade 4 changes so she also had Sjogren’s Syndrome diagnosis. After induction treatment, she received CTX regimen; but due to difficulty of use, AZA and hydroxychloroquine were started.

While using AZA, she presented with HSV Encephalitis approximately one month later. No case of HSV type 1 encephalitis after NMOSD has been reported in the literature. But as is known, immunosuppresive treatments might trigger possible viral infections. MRI was suggestive for HSV encephalitis and diagnosis was also confirmed by cerebrospinal fluid HSV PCR. On this time limbic panel from blood and CSF was negative. While she was in the hospital for IV treatment of acyclovir, the follow-up brain MRI which performed with the purpose of starting maintenence therapy for NMOSD, showed increased T2 hyperintensity and contrast enhancement on the left limbic area. In new CSF evaluation, anti-NMDAR antibody was found to be positive.

As reported in the literature before, herpes simplex encephalitis is a widely accepted risk factor for anti-NMDAR encephalitis. For treatment, seizure control and immunotherapy (first-line immunotherapy: steroids, IVIG, plasmapheresis, and second-line: RTX, CTX) are recommended. So after induction therapy, our patient was given RTX; and with the controlling of the seizures, her neurologic examination got better

Conclusions

This case provides evidence for the coexistance of NMOSD with anti-NMDAR encephalitis. Regarding previous case reports and studies, it is necessary to improve our understanding of effect relationship and pathogenesis of this comorbidity to guide both treatment and the prognosis.

Background

Management of Pediatric Onset Multiple Sclerosis (POMS) may be challenging. Three treatments are approved in Turkey: interferon-β, glatiramer acetate, fingolimod, other agents still being on off-label use.

Objectives

We aimed to evaluate POMS patients under new generation therapies (NGT) (teriflunomide, dimethyl fumarate, fingolimod, rituximab, ocrelizumab, natalizumab, alemtuzumab). We compared disease status and MRI parameters between patients under first-line injectable therapies or NGT as first choice.

Methods

POMS patients currently under NGT, either switched from an old injectable treatment (interferon-β or glatiramer acetate, Group1) or been under NGT from the beginning (Group2), were evaluated retrospectively. Their disease history, EDSS scores, imaging data before and after the NGT were evaluated. Brain and/or cervical MRIs were analyzed according to lesion load, lesion location, atrophy, Gadolinium (Gd) enhancing lesions, optic neuritis, spinal lesions.

Results

There were 41 patients (34 females: 7 males), 27 (65.9%) in Group1 and 14 (34.1%) in Group2. Mean age of onset was 14 (SD=2) years. Patients in Group1 switched to NGT mainly because of ineffectiveness (88.9%) while Group2 tended to stay under the same drug except 2 patients under teriflunomide switching to another NGT because of side effects. The NGTs in Group1 were fingolimod (n=13), DMF (n=7), teriflunomide (n=4), natalizumab (n=3) and in Group2, teriflunomide (n=11), dimethyl fumarate (n=2), fingolimod (n=1). Annualized relapse rate was 0.292 in Group1, 0.244 in Group2 (p=0.931). The MRI parameters and the follow up MRIs were not significantly different between Group1 and Group2. The current median EDSS scores were similar in both groups (1.5 and 0.5 respectively; p=0.171).

Conclusions

Fingolimod was the most frequently used NGT in patients where first-line drugs were ineffective and teriflunomide was the frequent choice if treatment was started with an NGT. Only a few patients needed second-line treatments as a first-choice option in our POMS group. We did not observe any significant difference between clinical and MRI status among POMS patients under the first-line of newer drugs, although the latter was associated with a slightly lower EDSS score.