Background

Tumefactive multiple sclerosis (MS) is a rare entity that occurs in approx. 1 per 1000 cases of MS and presents a significant diagnostic challenge due to clinical and radiologic similarities with several inflammatory, infectious and neoplastic processes. It usually occurs as a first clinical event but has been observed in patients on modern immunosuppressants, such as fingolimod.

Objectives

To report a case of possible adverse effect of a disease-modifying therapy for MS._______________________________

Methods

Case report__________________________________________________________________________________________

Results

A 49-year old male patient was diagnosed with RRMS in 2017 after a brainstem relapse with typical radiologic features on MRI and positive oligoclonal bands in CSF. He started on ocrelizumab in Feb 2018 and was clinically and radiographically stable until spring 2020 with an EDSS of 1.0.

He noticed subtle clumsiness in his left hand at the beginning of April 2020 and presented to our Emergency unit approximately 3 weeks later. Neurological examination revealed mild dysarthria and mild left-sided hemiparesis with hemihypesthesia and an EDSS score of 3.5.

An emergency brain MRI was performed and revealed 2 new large T2 and FLAIR hyperintense lesions in bilateral frontal white matter with central contrast enhancement, diffuse T2 and FLAIR hyperintense lesions in cerebellar white matter and patchy granular thick leptomeningeal enhancement in cerebellar folia.

CSF examination showed mildly elevated proteins with mild lymphocytosis. JC virus DNA PCR in CSF was negative as were all other initial microbiological tests. CSF cytology revealed reactive lymphocytosis without evidence of malignancy. Follow up MRI showed worsening of the leptomeningeal enhancement in the posterior fossa and persistent large supratentorial lesions. The patient was then empirically treated with steroids yet failed to improve initially.

An extensive CSF and serological panel excluded possible infectious diseases and rheumatic diseases. Antineuronal and paraneoplastic antibodies in CSF and serum were negative. A brain biopsy revealed activated T cells, with no signs of demyelination-possibly due to peripheral sampling. Follow-up MRI showed regression of leptomeningeal enhancement. A repeated lumbar puncture was again negative for malignant cells. He was treated with steroids with signs of improvement which were afterwards withheld for 4 weeks for the second brain biopsy which again revealed inflammatory demyelination with the absence of B cells with activated T cells and no malignant cells. He has been afterwards continuing with steroids with slow improvement of symptoms.

Conclusions

We presented a RRMS patient who developed tumefactive lesions while on B-cell monoclonal antibody therapy, possibly due to immune dysregulation. We cannot fully exclude underlying CNS lymphoma and will continue to follow him closely.

Background

With the arrival of disease modifying treatment for primary progressive multiple sclerosis (PPMS), biomarkers of unfavorable outcome are badly needed. Neuropathologically, PPMS is characterized by diffuse and compartmentalized low-grade inflammation with microglial activation. A microglia-related marker, cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1), was shown to predict disability progression in relapsing-remitting MS, but has not been studied extensively in progressive forms of disease.

Objectives

We aimed to evaluate the prognostic potential of CSF biomarkers reflecting microglial activation (CHI3L) and neuroaxonal damage (neurofilaments light chain, NFL) in our cohort of PPMS patients.

Methods

Thirty-eight PPMS patients (24 women) with median age of 54 years (range 34,5 – 72,9 years) were admitted to our department between 2013-2020. They presented with a median 3-years (range 0.5-30-year) history of spastic paraparesis and had basic CSF analysis with CSF cell count, albumin quotient, oligoclonal bands (OCB) and quantitative IgG and IgM synthesis done at the time of diagnosis. One-year follow-up data with Extended Disability Status Scale (EDSS) were available for 30 patients. CSF CHI3L1 and NFL were measured by enzyme-linked immunosorbent assays (Quantikine ELISA kit, R&D Systems Inc. and UmanDiagnostics AB, respectively). The Spearman’s rho test was used to test for associations between CSF biomarkers and disability progression.

Results

All patients had typical brain MRI lesions (74% more than 10, 83% also spinal cord lesions) and in 90% OCB were detected. At follow-up, nearly one half (n=14) of the patients showed EDSS progression of at least 0.5 points. Despite the correlation between CSF CHI3L1 and NFL levels (ρ = 0.543, p < 0.01), CHI3L1, but not NFL, was significantly higher in patients with EDSS progression (176 ng/ml vs. 235 ng/ml, p < 0.01) and correlated with one-year EDSS change (ρ = 0.407, p = 0.025). A moderate negative correlation between CHI3L1 and disease duration was also observed (ρ = -0.370, p = 0.02) as well as association with CSF cell count and IgG intrathecal synthesis (ρ = 0.465, p < 0.01). CHI3L1 was not related with the number of MRI lesions at the time of diagnosis.

Conclusions

CHI3L1 was associated with disease duration and disability progression in PPMS patients. Its prognostic biomarker potential for this disabling form of MS should be further studied in a larger, prospective study cohort.