SUMMARY – Multiple sclerosis (MS) is a multicomponent disease characterized by inflammation, neurodegeneration, and cancellation of the central nervous system recovery mechanisms. The cause of MS is still unknown, but it is undeniable that genetic, environmental and immune factors are involved in the etiopathogenesis of this complex and heterogeneous disease. From the aspect of immunopathogenesis, until recently the opinion prevailed that autoreactive T lymphocytes played a major role, the activation of which is a key step in MS. The knowledge of the effector and regulatory roles of B cells supports a new concept of MS immunopathogenesis that is based on the highly complex interaction of T and B cells, with B cells actively participating in cellular immunity by directing the intensity and quality of cellular immune response. The mechanisms of B cell activity in MS immunopathogenesis are multiple and include antigen presentation and T cell costimulation, cytokine secretion, antibody synthesis, and formation of ectopic lymphoid B cell aggregates in the intrameningeal spaces. The importance of B cells has been confirmed by modern therapeutic options for the treatment of MS.

Objectives: Receptor for advanced glycation end products (RAGE) ligands/RAGE interactions have been proposed to have a pathogenic role in neuroinflammatory disorders. Our study aimed to assess changes in high-mobility group box (HMGB)1 and its receptor RAGE in peripheral blood (PBL) and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) at the disease onset compared with control subjects. Methods: PBL and CSF were collected from control subjects (n = 30) and MS patients (n = 27) at clinical onset. Soluble RAGE (sRAGE), HMGB1, S100 calcium-binding protein A12 (S100A12), interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured in the CSF and plasma by enzyme-linked immunosorbent assay. Gene expression in PBL mononuclear cells (PBMCs) was detected by quantitative PCR for RAGE, HMGB1, S100A12 and several proinflammatory/immunoregulatory cytokines. Results: We found a significantly lower expression of IL-10 (p = 0.031) in the PBMCs of MS patients. The level of sRAGE in the CSF of MS patients was lower (p = 0.021), with the ability to discriminate between MS patients and control subjects. Moreover, PBMC gene expression for HMGB1 and S100A12 positively correlated with IL-6. Conclusions: Our study confirmed that the cytokine network is disturbed in PBL and CSF at MS clinical onset. The deregulated HMGB1/RAGE axis found in our study may present an early pathogenic event in MS, proposing sRAGE as a possible novel therapeutic strategy for MS treatment.

Acute disseminated encephalomyelitis (ADEM) is an idiopathic inflammatory demyelinating disease of the CNS that is particularly difficult to differentiate from the first episode of multiple sclerosis. ADEM typically occurs as a post-infectious phenomenon, and usually presents a monophasic episode, but also includes recurrent and multiphasic forms. We report a case of ADEM associated with hepatitis B virus (HBV) reinfection. After steroid and IV immunoglobulin treatment, neurologic symptoms were improved. We suppose that the HBV reinfection was the cause of ADEM, but possible pathogenetic mechanism is still obscure.

Coronavirus disease 2019 (COVID-19), caused by the late 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a respiratory disease which could put myasthenia gravis (MG) patients at a greater risk of developing severe disease course, since infections and some drugs are a well-recognized trigger of symptom exacerbation in MG patients. Out of ten most commonly used past and present drugs used in COVID-19 treatment, two (quinolone derivatives and azithromycin) are known to worsen MG symptoms, whereas another two (tocilizumab and eculizumab) might have positive effect on MG symptoms. Colchicine, remdesivir, lopinavir, ritonavir and favipiravir seem to be safe to use, while data are insufficient for bamlanivimab, although it is also probably safe to use. Considering MG treatment options in patients infected with SARS-CoV-2, acetylcholine esterase inhibitors are generally safe to use with some preliminary studies even demonstrating therapeutic properties in regard to COVID-19. Corticosteroids are in general safe to use, even recommended in specific circumstances, whereas other immunosuppressive medications (mycophenolate mofetil, azathioprine, cyclosporine, methotrexate) are probably safe to use. The only exception is rituximab since the resulting B cell depletion can lead to more severe COVID-19 disease. Concerning plasmapheresis and intravenous immunoglobulins, both can be used in COV-ID-19 while taking into consideration thromboembolic properties of the former and hemodynamic disturbances of the latter. As current data suggest, all known COVID-19 vaccines are safe to use in MG patients.

Spontaneous intracranial hypotension is a rare condition caused by spontaneous cerebrospinal fluid leak and volume depletion. It is initially misdiagnosed as a cause of an orthostatic headache, which is the most important symptom of the syndrome. It can be presented as one of four types: classic form, normal pressure form, normal pachymeninges form and acephalgic form. The diagnosis is made based on the clinical presentation, physical examination, typical cerebrospinal fluid and magnetic resonance imaging findings. We present a case of a 29-year-old woman with uncommon normal pressure form of the spontaneous intracranial hypotension, characterized by normal cerebrospinal fluid opening pressure, and typical clinical and magnetic resonance imaging findings, including the finding of pituitary gland enlargement with asymptomatic pituitary haemorrhage as an unusual complication.

Untreated multiple sclerosis (MS) irretrievably leads to severe neurological impairment. In European health care systems, patient access to disease modifying therapies (DMT) is often confined to more advanced stages of the disease because of restrictions in reimbursement. A discrepancy in access to DMTs is evident between West and East European countries. In order to improve access to DMTs for people with MS (pwMS) living in Croatia, the Croatian Neurological Society issued new recommendations for the treatment of relapsing MS. The aim of this article is to present these recommendations. The recommendations for platform therapies are to start DMT as soon as the diagnosis is made. If poor prognostic criteria are present (≥9 T2 or FLAIR lesions on the initial brain and spinal cord magnetic resonance imaging [MRI] or ≥3 T1 lesions with postcontrast enhancement on the initial brain and spinal cord MRI or Expanded Disability Status Scale after treatment of the initial relapse ≥3), high-efficacy DMT should be initiated. If pwMS experience ≥1 relapse or ≥3 new T2 lesions while on platform therapies, they should be switched to high-efficacy DMT. Further efforts should be made to enable early and unrestricted access to high-efficacy DMT with a freedom of choice of an appropriate therapy for expert physicians and pwMS. The improvement of access to DMT achieved by the implementation of national treatment guidelines in Croatia can serve as an example to national neurological societies from other Eastern European countries to persuade payers to enable early and unrestricted treatment of pwMS.

The BNT162b2 (Pfizer BioNTech) mRNA vaccine is an effective vaccine against COVID-19 infection. Here, we report an adverse event following immunization (AEFI) in a 48-year-old female patient who presented with fasciculations, migraine auras without headaches and in an increased discomfort of previously present palpitations, as well as excitation and insomnia. Her fasciculations were intermittently present until the time this paper was written, starting from the 6th day post-vaccination; they changed localization and frequency, but most commonly they were generalized, affecting almost all muscle groups. The patient also suffered from two incidents of migraine auras with visual kaleidoscope-like phenomena without headaches a few months after the vaccination. These symptoms were considered to be AEFI and no causal relation with the vaccine could be proven.

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