Treatment of Multiple Sclerosis During the COVID-19 Pandemic

Za liječenje relapsno-remitirajućeg oblika MS-a (RRMS) odobreno je više lijekova koji modificiraju tijek bolesti (DMT). Postoje dva pristupa u liječenju MS-a. Jedan pristup je kontinuirana primjena terapije (tzv. terapija održavanja), a koja se onda može optimizirati ovisno o tijeku bolesti. U terapiju održavanja spadaju interferoni beta, glatiramer acetat, teriflunomid, dimetilfumarat, natalizumab, modulatori S1P receptora (fingolimod) te okrelizumab. Drugi noviji pristup u liječenju MS-a je imunorekonstitucijski. U imunorekonstitucijsku terapiju spadaju alemtuzumab i kladribin. Općenito se može reći kako, osim beta-interferona i glatiramer acetata, svi ostali DMT su u različitim stupnjevima povezani s rizikom od infekcije. Upravo ovaj povećani rizik od infekcija kod osoba s MS-om koje primaju različite DMT postao je vrlo aktualan uslijed pandemije COVID-19. Potrebno je naglasiti kako trenutno ne znamo jesu li osobe s MS-om izložene povećanom riziku da dobiju COVID-19 ili da razviju teški oblik COVID-19 bolesti. Također, ne postoje znanstveni dokazi o tome koji DMT koji koristimo u liječenju MS-a utječe na mogućnost zaraze ili tijek COVID-19 infekcije. Jasno je da će svaku odluku o početku primjene DMT-a tijekom pandemije COVID-19 trebati pažljivo donijeti i ovisit će o stanju pandemije COVID-19, ne samo u određenoj zemlji, već i na specifičnom području gdje osoba živi i prima terapiju. Pri tome potrebno je voditi računa o proaktivnom pristupu liječenja MS-a, usredotočiti se na osobu s MS-om u svim fazama bolesti kako bi se posljedice bolesti svele na minimum te povećala kvaliteta života.Multiple disease-modifying therapies (DMTs) have been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). There are two approaches to treating MS. One approach is the continuous application of therapy (maintenance therapy), which can then be optimized depending on the course of the disease. Maintenance therapy includes interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab, S1P receptor modulators (fingolimod), and ocrelizumab. Another recent approach in the treatment of MS is immune reconstitution therapy. Immune reconstitution therapy includes alemtuzumab and cladribine. In general, with the exception of beta-interferon and glatiramer acetate, all other DMTs are associated with varying degrees of risk of infection. It is this increased risk of infection in MS with various DMTs that has become very relevant in the COVID-19 pandemic. It should be emphasized that we do not currently know whether people with MS are at increased risk of catching COVID-19 or developing severe COVID-19 disease. There is also no scientific evidence that the DMTs we use to treat MS affect the possibility of infection or the course of COVID-19 infection. Clearly, any decision to initiate DMTs during the COVID-19 pandemic must be made carefully and will depend on the state of the pandemic, not only in a specific country but also in a specific area where a person lives and receives therapy. In doing so, care should be taken to take a proactive approach to MS treatment and focus on the patient at all stages of the disease, in order to minimize its aftereffects and maximize the quality of life

Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications

Multiple sclerosis is characterized by a wide spectrum of clinical manifestations, among which dysfunction of the autonomic nervous system represents an important cause of multiple sclerosis-related disability. The aim of this review is to provide an overview of autonomic dysfunction in people with multiple sclerosis, and to discuss the interactions between the immune and autonomic nervous systems and the effects of these interactions on various aspects of multiple sclerosis. Autonomic dysfunction in people with multiple sclerosis can be demonstrated clinically and on a molecular level. Clinically, it can be demonstrated by measuring autonomic symptoms with the Composite Autonomic Symptom Score (COMPASS-31), and neurophysiologically, with different autonomic nervous system tests. Both symptomatic and objectively determined autonomic dysfunction can be associated with increased risk of multiple sclerosis disease activity. Further supporting these clinical observations are molecular changes in immune cells. Changes in the sympathetic autonomic system, such as different expression of dopaminergic and adrenergic receptors on immune cells, or modulation of the cholinergic anti-inflammatory pathway over different subunits of the nicotinic acetylcholine receptor in the peripheral immune system, may mediate different effects on multiple sclerosis disease activity

Psychiatric manifestations of multiple sclerosis and acute disseminated encephalomyelitis

It is unusual for acute disseminated encephalomyelitis and multiple sclerosis to present as purely psychiatric disorders. We report five patients with such demyelinating diseases and symptoms of psychosis, depression or anxiety. The importance of excluding demyelination as the basis for these psychiatric disturbances is emphasized, especially in the presence of unexplained neurologic findings. The possible relationship between psychiatric symptoms and demyelinating disorders is explored

Primjena genomske analize u istraživanju biomarkera razvoja multiple skleroze u bolesnika s optičkim neuritisom

Introduction: Development of gene markers which are able to determin risk for development of MS after optic neuritis, would be of particular importance in early diagnosis and therapeutic intervention in patients with multiple sclerosis. Therfore, our hypothesis was that gene microarray analysis of whole blood samples in patients with acute optic neuritis will determine differentially expressed genes which can serve as potential gene markers for diagnosis and follow-up of multiple sclerosis. ----- Materials and methods: We included 15 patients with acute optic neuritis and 10 healthy controls. Gene expression was analyzed with DNA microarrays for whole human genome analysis (Human Genome U133 PLUS 2.0 GeneChip, Affymetrix) which contains 54 675 25-base pairs. Results of 9 selected genes were confirmed with PCR. Aditional analysis was performed with gene ontology analysis and GSEA. ----- Results: This is the first study of whole genome expression analysis of whole blood in patients with optic neuritis. Totally 722 genes with different expression were identified , 377 with increased expression and 345 with decreased expression profiles. Based on statistical significance and up to know known involvement in MS, from 722 genes, 9 were selected as potential biomarkers, 5 with increased expression (PTPRC, SLC11A1, SLPI, NAIP, LPXN) and 4 with decreased expression (CCR3, ITGA4, CD28, SLAMF7). Gene ontology analysis and GSEA showed that protein phosphorilation and intracelular compartment, apoptosis inhibition, and pathways involved in cell cycles, T- and B-cell functions and anti-inflammatory CNS pathways are implicated in MS pathology. ----- Conclusion: Gene expression analysis of whole blood showed significant differences in expression profiles of patients with optic neuritis compared with healthy control. As well, pathways involved in T-cell regulation and anti-inflammatory pathways within CNS are identified as important in early phases of MS

New Approach to the Treatment of Multiple Sclerosis

Danas je za liječenje relapsno remitirajuće multiple skleroze (RRMS) odobreno više od 10 lijekova, od kojih su neki blage do umjerene učinkovitosti, ali dobra sigurnosnog profila, a neki visoke učinkovitosti, no lošijega sigurnosnog profila. S obzirom na velik broj dostupne terapije, problem je kako se odlučiti za optimalno liječenje bolesnika s RRMS-om. Ponajprije je potrebno znati mehanizam djelovanja lijeka, podatke o njegovoj učinkovitosti na smanjenje broja relapsa i napredovanja neurološke onesposobljenosti te sigurnosni profil lijeka kako bi se ispravno mogli staviti u odnos korist i rizici od liječenja svakim od navedenih lijekova. Podaci iz kliničke prakse govore da samo određeni broj bolesnika odgovori na pojedini lijek, što znatno otežava odabir odgovarajućeg lijeka za svakog bolesnika. Štoviše, unatoč velikom napretku u liječenju multiple skleroze još ne postoji biomarker koji bi nam na individualnoj razini omogućio odabir lijeka što bi najviše odgovarao pojedinom bolesniku. Odabir lijeka ovisi o aktivnosti bolesti koja se najčešće definira s pomoću relapsa, zatim stupnja onesposobljenosti koji se mjeri EDSS-om (Expanded Disability Status Scale) te nalaza magnetske rezonancije (broj i volumen lezija T2, broj lezija T1 koje se imbibiraju nakon primjene kontrastnog sredstva). Međutim, unatoč brojnim pokazateljima aktivnosti bolesti još nema jasno prihvaćenih kriterija kako definirati niskoaktivan ili visokoaktivan oblik RRMS-a. Također, postoji problem kako prepoznati bolesnika na samom početku bolesti, koji će poslije imati teži tijek multiple skleroze. Postoje dva pristupa u liječenju te bolesti. Jedan je pristup kontinuirana primjena terapije (tzv. terapija održavanja), koja se onda može optimizirati ovisno o tijeku bolesti. Ovakav eskalacijski pristup liječenju može se razvijati na dva načina koji ovise o aktivnosti bolesti. Kod osoba s visokoaktivnom multiplom sklerozom kreće se s lijekom visoke učinkovitosti odmah od početka bolesti, čak i u fazi klinički izoliranog sindroma ako postoje negativni prognostički čimbenici. Za razliku od navedenoga, kod osoba s blagim oblikom multiple skleroze liječenje započinjemo lijekovima umjerene učinkovitosti, ali odlična sigurnosnog profila, a tek ako oni zataje, odlučujemo se za lijekove jače učinkovitosti, ali lošijega sigurnosnog profila. Obilježja su ovog pristupa da bolesnik mora kontinuirano primati terapiju. Drugi pristup liječenju jest imunorekonstitucijski, pri kojemu pulsnom imunosnom rekonstitucijom dovodimo do (prolaznog ili trajnog) resetiranja imunosnog sustava s potencijalom trajne remisije. Nakon primjene jednog od takvih lijekova bolesnik može biti bez ikakve terapije, dobivati dodatne cikluse istog lijeka prema potrebi ili nastaviti terapiju održavanja nekim od lijekova umjerene učinkovitosti, ali odličnoga sigurnosnog profila.Currently, more than 10 different drugs have been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Some of them have slight to moderate efficacy combined with a good safety profile, whereas others have high efficacy, but a less favourable safety profile. Numerous therapeutic options available make it difficult to choose optimum treatment for patients with RRMS. In order to properly assess the benefits and risks of treatment with each of the specified drugs, it is necessary to know a drug’s mechanism of action, data on its efficacy in reducing the relapse rate and disability progression, as well as its safety profile. Clinical practice data indicate that only a certain number of patients respond to a drug, thus making the choice of an appropriate drug for each patient very difficult. Furthermore, despite major breakthroughs in the treatment of MS, there is still no biomarker that could enable individualized selection of a drug best suited for a patient. Selection of a drug depends on the disease activity, which is generally defined on the basis of relapse rate, on the disability status measured on the Expanded Disability Status Scale (EDSS) and on the MRI findings (number and volume of T2 lesions, number of T1 contrast-enhanced lesions). However, despite numerous indicators of disease activity, there are still no clear accepted criteria to define RRMS as mildly or highly active. Another challenge is identifying patients during the early stage of MS who are likely to develop a more severe form of the disease. There are two therapeutic approaches to the treatment of MS. The first approach implies continuous treatment (i.e. maintenance therapy) which can be optimised depending on the course of the disease. Such escalation therapy can be carried out in two ways depending on the activity of the disease. Patients with highly active MS begin treatment with high efficacy drugs right from the onset of the disease, even during the clinically isolated syndrome, if the prognostic factors are negative. In contrast, patients with mild MS start treatment with drugs demonstrating moderate efficacy and excellent safety profile. When such drugs are no longer effective, patients are switched to high efficacy drugs with a less favourable safety profile. This approach implies that patients receive continuous treatment. The second approach involves immune reconstitution where pulse immune therapy is used to (temporarily or permanently) reset the immune system, potentially leading to permanent remission. After receiving one of these drugs, the patient can continue without treatment, receive additional cycles of the same drug as required, or continue to receive maintenance treatment with one of the drugs demonstrating moderate efficacy and excellent safety profile

NEOPSTETRIČKI SPONTANI RAZDOR KORONARNE ARTERIJE MATERNIČNOG SUBSEROZNOG MIOMA: PRIKAZ BOLESNICE I PREGLED LITERATURE

This is a report of a case of arterial bleeding from spontaneous nonobstetric uterine myoma, with review of the literature. A 38-year-old multipara with myomatous uterus presented with spontaneous abdominal pain, nausea and malaise, free from comorbidities and abdominal trauma. After emergency diagnostic workup, urgent laparotomy with supracervical hysterectomy was performed with uneventful course. Hemoperitoneum resulting from spontaneous nonobstetric rupture of the uterine myoma artery is exceptionally rare. Despite its rarity, it should be included in the differential diagnosis of the known myomatous uterus, acute abdominal pain and nonobstetric hemoperitoneum.Prikazan je slučaj i literaturni pregled spontanih neopstetričkih arterijskih krvarenja materničnih mioma. Bolesnica, 38-godišnja višerotkinja s miomatoznom maternicom u anamnezi, zaprimljena je sa spontanim bolovima, mučninom i slabošću, bez podataka o trbušnoj traumi, bez komorbiditeta. Nakon hitne obrade učinjena je hitna laparotomija sa supracervikalnom histerektomijom. Kako je hemoperitonej zbog spontanoga neopstetričkog razdora arterije materničnih mioma iznimno rijedak, akutna trbušna bol s neopstetričkim hemoperitonejem može upraviti dijagnozu u tom smjeru

NEOPSTETRIČKI SPONTANI RAZDOR KORONARNE ARTERIJE MATERNIČNOG SUBSEROZNOG MIOMA: PRIKAZ BOLESNICE I PREGLED LITERATURE

This is a report of a case of arterial bleeding from spontaneous nonobstetric uterine myoma, with review of the literature. A 38-year-old multipara with myomatous uterus presented with spontaneous abdominal pain, nausea and malaise, free from comorbidities and abdominal trauma. After emergency diagnostic workup, urgent laparotomy with supracervical hysterectomy was performed with uneventful course. Hemoperitoneum resulting from spontaneous nonobstetric rupture of the uterine myoma artery is exceptionally rare. Despite its rarity, it should be included in the differential diagnosis of the known myomatous uterus, acute abdominal pain and nonobstetric hemoperitoneum.Prikazan je slučaj i literaturni pregled spontanih neopstetričkih arterijskih krvarenja materničnih mioma. Bolesnica, 38-godišnja višerotkinja s miomatoznom maternicom u anamnezi, zaprimljena je sa spontanim bolovima, mučninom i slabošću, bez podataka o trbušnoj traumi, bez komorbiditeta. Nakon hitne obrade učinjena je hitna laparotomija sa supracervikalnom histerektomijom. Kako je hemoperitonej zbog spontanoga neopstetričkog razdora arterije materničnih mioma iznimno rijedak, akutna trbušna bol s neopstetričkim hemoperitonejem može upraviti dijagnozu u tom smjeru

Do we need broad immunological work-up in all patients with CIS?

BACKGROUND: The aim of this study was to determine the prevalence of altered immunological tests and their clinical significance in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). ----- PATIENTS AND METHODS: The information was gathered from medical records of patients hospitalized in the Referral Center for Demyelinating Diseases in the 2008-2010 period. All patients had ANA, ENA profile, ANCA, aCl IgG and IgM, C3, C4, CH50, anti-TPO, AST and RF antibodies tested. ----- RESULTS: From 726 patients with CIS that were reviewed, the complete battery of immunological tests was performed in 418 of them (57.6%), representing our cohort. Altered tests were found in 235 patients (56.2%); 73 (17.4%) had positive antinuclear antibodies, 14 (3.3%) had positive ENA, 47 (11.2%) had positive aCl IgG, 83 (19.8%) had positive aCl IgM, and 13 (3.1%) had anti TPO antibodies. We found no correlation between ANA, aCl IgG or IgM positivity (ANA vs aCL IgG p=0.554; ANA vs aCL IgM p=0.19; aCL IgG vs aCL IgM, p=0.155). None of the patients had any clinical manifestations other than MS symptoms. ----- CONCLUSION: These results indicate that significant number of patients with CIS have altered immunological tests but nevertheless none of them had clinical expression of any other autoimmune disease making them clinically insignificant. In conclusion there is no need to perform extensive immunological work-up in all patients with CIS. Contrary, our results argue for more focused testing rather than a battery of screening tests