Do Hungarian multiple sclerosis care units fulfil international criteria?

Zsófia Kokas; Dániel Sandi; Zsanett Fricska-Nagy; Judit Füvesi; Tamás Biernacki; Ágnes Köves; Ferenc Fazekas; Adrienne Jóri Birkás; Gabriella Katona; Krisztina Kovács; Dániel Milanovich; Enikő Dobos; István Kapás; Gábor Jakab; Tünde Csépány; Erzsébet Bense; Klotild Mátyás; Gábor Rum; Zoltán Szolnoki; István Deme; Zita Jobbágy; Dávid Kriston; Zsuzsanna Gerócs; Péter Diószeghy; László Bors; Adrián Varga; Levente Kerényi; Gabriella Molnár; Piroska Kristóf; Zsuzsanna Ágnes Nagy; Mária Sátori; Piroska Imre; Szilvia Péntek; Péter Klivényi; Zsigmond Tamás Kincses; László Vécsei; Krisztina Bencsik

doi:10.1371/journal.pone.0264328

. 2022 Mar 3;17(3):e0264328. doi: 10.1371/journal.pone.0264328

Do Hungarian multiple sclerosis care units fulfil international criteria?

Zsófia Kokas ¹, Dániel Sandi ¹, Zsanett Fricska-Nagy ¹, Judit Füvesi ¹, Tamás Biernacki ¹, Ágnes Köves ², Ferenc Fazekas ³, Adrienne Jóri Birkás ⁴, Gabriella Katona ⁵, Krisztina Kovács ⁶, Dániel Milanovich ⁷, Enikő Dobos ⁸, István Kapás ⁹, Gábor Jakab ¹⁰, Tünde Csépány ¹¹, Erzsébet Bense ¹², Klotild Mátyás ¹³, Gábor Rum ¹⁴, Zoltán Szolnoki ¹⁵, István Deme ¹⁶, Zita Jobbágy ¹⁷, Dávid Kriston ¹⁸, Zsuzsanna Gerócs ¹⁹, Péter Diószeghy ²⁰, László Bors ²¹, Adrián Varga ²², Levente Kerényi ²³, Gabriella Molnár ²⁴, Piroska Kristóf ²⁵, Zsuzsanna Ágnes Nagy ²⁶, Mária Sátori ²⁷, Piroska Imre ²⁸, Szilvia Péntek ²⁹, Péter Klivényi ¹, Zsigmond Tamás Kincses ^1,³⁰, László Vécsei ^1,³¹, Krisztina Bencsik ^1,^*

Editor: Marcello Moccia³²

¹Faculty of General Medicine, Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary

²Department of Neurology, Bajcsy-Zsilinszky Hospital, Budapest, Hungary

³Department of Neurology, Gyula Nyírő Hospital and National Institute of Psychiatry and Addictions, Budapest, Hungary

⁴Department of Neurology, National Institute of Clinical Nerosciences, Budapest, Hungary

⁵Department of Neurology, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary

⁶Department of Neurology, Péterfy Hospital, Budapest, Hungary

⁷Department of Neurology, Semmelweis University, Budapest, Hungary

⁸Department of Neurology, Saint Imre Hospital and University Teaching Hospital, Budapest, Hungary

⁹Department of Neurology, Saint János Hospital, Budapest, Hungary

¹⁰Department of Neurology, Uzsoki Hospital, Budapest, Hungary

¹¹Division of Neurology, University of Debrecen Clinical Center, Debrecen, Hungary

¹²Department of Neurology, University of Debrecen Faculty of Medicine, Debrecen, Hungary

¹³Department of Neurology, Ferenc Markhot Teaching Hospital, Eger, Hungary

¹⁴Department of Neurology, Aladár Petz University Teaching Hospital, Győr, Hungary

¹⁵Department of Neurology, Kálmán Pándy County Hospital, Gyula, Hungary

¹⁶Department of Neuology, Mór Kaposi Teaching Hospital, Kaposvár, Hungary

¹⁷Department of Neurology, Kecskemét County Hospital, Kecskemét, Hungary

¹⁸Department of Neurology, Borsod-Abaúj-Zemplén County Central Hospital and University Teaching Hospital, Miskolc, Hungary

¹⁹Department of Neurology, Dorottya Kanizsai Hospital, Nagykanizsa, Hungary

²⁰Department of Neurology, Aladár Jósa Teaching Hospital, Nyíregyháza, Hungary

²¹Department of Neurology, University of Pécs Clinical Center Pécs, Pécs, Hungary

²²Department of Neurology, Saint Lázár County Hospital, Salgótarján, Hungary

²³Department of Neurology, Fejér County Saint György University Teaching Hospital, Székesfehérvár, Hungary

²⁴Department of Neurology, János Balassa Hospital, Szekszárd, Hungary

²⁵Department of Neurology, Jász-Nagykun-Szolnok County Géza Hetényi Hospital, Szolnok, Hungary

²⁶Department of Neurology, Markusovszky University Teaching Hospital, Szombathely, Hungary

²⁷Department of Neurology, Saint Borbála Hospital, Tatabánya, Hungary

²⁸Department of Neurology, Ferenc Csolnoky Hospital, Veszprém, Hungary

²⁹Department of Neurology, Zala County Saint Rafael Hospital, Zalaegerszeg, Hungary

³⁰Faculty of General Medicine, Department of Radiology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary

³¹MTA-SZTE Neuroscience Research Group, Szeged, Hungary

³²Universita degli Studi di Napoli Federico II, ITALY

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: bencsik.krisztina@med.u-szeged.hu

Roles

Zsófia Kokas: Data curation, Formal analysis, Project administration, Visualization, Writing – original draft

Dániel Sandi: Project administration, Visualization, Writing – review & editing

Zsanett Fricska-Nagy: Writing – review & editing

Judit Füvesi: Writing – review & editing

Tamás Biernacki: Writing – review & editing

Ágnes Köves: Resources, Writing – review & editing

Ferenc Fazekas: Resources, Writing – review & editing

Adrienne Jóri Birkás: Resources, Writing – review & editing

Gabriella Katona: Resources, Writing – review & editing

Krisztina Kovács: Resources, Writing – review & editing

Dániel Milanovich: Resources, Writing – review & editing

Enikő Dobos: Resources, Writing – review & editing

István Kapás: Resources, Writing – review & editing

Gábor Jakab: Resources, Writing – review & editing

Tünde Csépány: Resources, Writing – review & editing

Erzsébet Bense: Resources, Writing – review & editing

Klotild Mátyás: Resources, Writing – review & editing

Gábor Rum: Resources, Writing – review & editing

Zoltán Szolnoki: Resources, Writing – review & editing

István Deme: Resources, Writing – review & editing

Zita Jobbágy: Resources, Writing – review & editing

Dávid Kriston: Resources, Writing – review & editing

Zsuzsanna Gerócs: Resources, Writing – review & editing

Péter Diószeghy: Resources, Writing – review & editing

László Bors: Resources, Writing – review & editing

Adrián Varga: Resources, Writing – review & editing

Levente Kerényi: Resources, Writing – review & editing

Gabriella Molnár: Resources, Writing – review & editing

Piroska Kristóf: Resources, Writing – review & editing

Zsuzsanna Ágnes Nagy: Resources, Writing – review & editing

Mária Sátori: Resources, Writing – review & editing

Piroska Imre: Resources, Writing – review & editing

Szilvia Péntek: Resources, Writing – review & editing

Péter Klivényi: Writing – review & editing

Zsigmond Tamás Kincses: Writing – review & editing

László Vécsei: Conceptualization, Methodology, Writing – review & editing

Krisztina Bencsik: Conceptualization, Methodology, Supervision, Writing – review & editing

Marcello Moccia: Editor

PMCID: PMC8893632 PMID: 35239686

Abstract

A patients

Because of the past 3 decades’ extensive research, several disease modifying therapies became available, thus a paradigm change is multiple sclerosis care was necessary. In 2018 a therapeutic guideline was created recommending that treatment of persons with multiple sclerosis should take place in specified care units where the entire spectrum of disease modifying therapies is available, patient monitoring is ensured, and therapy side effects are detected and treated promptly. In 2019 multiple sclerosis care unit criteria were developed, emphasizing personnel and instrumental requirements to provide most professional care. However, no survey was conducted assessing the real-world adaptation of these criteria.

Objective

To assess whether Hungarian care units fulfil international criteria.

Methods

A self-report questionnaire was assembled based on international guidelines and sent to Hungarian care units focusing on 3 main aspects: personnel and instrumental background, disease-modifying therapy use, number of people living with multiple sclerosis receiving care in care units. Data on number of persons with multiple sclerosis were compared to Hungarian prevalence estimates. Descriptive statistics were used to analyse data.

Results

Out of 27 respondent care units, 3 fulfilled minimum requirements and 7 fulfilled minimum and recommended requirements. The least prevalent neighbouring specialties were spasticity and pain specialist, and neuro-ophthalmologist and oto-neurologist. Only 15 centres used all available disease modifying therapies. A total number of 7213 people with multiple sclerosis received care in 27 respondent centres. Compared to prevalence estimates, 2500 persons with multiple sclerosis did not receive multiple sclerosis specific care in Hungary.

Conclusion

Less than half of Hungarian care units provided sufficient care for people living with multiple sclerosis. Care units employing fewer neighbouring specialties, might have difficulties diagnosing and providing appropriate care for persons with multiple sclerosis, especially for people with progressive disease course, contributing to the reported low number of persons living with multiple sclerosis.

1. Introduction

1.1. Background

Multiple Sclerosis (MS) is an autoimmune demyelinating neurodegenerative disorder of the central nervous system (CNS), which usually affects young adults [1]. Although MS is a rare disease, it affects roughly 2.8 million people worldwide [2] and is one of the most cost-expensive diseases to treat nowadays [3]. Without appropriate treatment, people with MS develop physical and cognitive impairment, as well as other psychopathological anomalies, such as depression, anxiety and fatigue, which all significantly diminish working ability, societal relationships and quality of life [4].

1.2. First therapy and its effects on the management of persons living with multiple sclerosis

The very first therapy approved in the treatment of MS was interferon-β-1b (IFN-β-1b) [5], which was licensed in the European Union (EU) in 1995. In the EU, persons with MS were prescribed IFN-β-1b by local neurologists and were provided with their medication according to the funding protocol of national insurance companies. After prescribing the disease modifying therapy (DMT), management of people living with MS was provided by general practitioners (GP) and in some cases care of persons living with MS took place in University Departments to participate in clinical research. Because of the differences in resources, health care system and legal background among countries, MS care could not have been standardized, and since then vast differences occurred in management of people with MS.

1.3. Management of people living with multiple sclerosis in Hungary

DMT prescribing in Hungary was approached differently because of the high retail price of the disease modifying therapies. Disease specific therapy prescription was allowed by the National Health Insurance Fund (NHIF) if MS care was pursued in specialized MS centres. Thus, specialized MS centre conditions had to be determined by the Hungarian Neurological Professional College in 1996 (Table 1).

Table 1. Specialized MS centre conditions determined by the Hungarian Neurological Professional College.

Hungarian MS centre conditions

1. The neurological department should have a separate outpatient unit dedicated only for persons with MS, with at least 6 consulting hours a week.
2. At least 2 neurologists with experience in treating MS and at least 1 specially trained MS nurse should be employed.
3. The centre should have the conditions to properly examine, diagnose, and treat people with MS.
4. Documentation should include patient history, annual relapse rate change after DMT initiation, change of physical status (Expanded Disability Status Scale) while receiving DMT
5. Eligibility to treatment was approved by an independent board of professionals thoroughly reviewing disease history recorded in documentation.

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Abbreviations: DMT = disease modifying therapy, MS = multiple sclerosis.

In that guideline besides professional criteria, patient’s equality was also taken into consideration. In this manner, the four Hungarian University Departments, county hospitals and some regular city hospitals in the capital city (26 in total), were designated to participate in MS care. Since then, this number steadily increased to 31 (Fig 1). In the past 25 years Hungarian MS centres have operated according to Neurological Professional College’s guideline. However, in this period classification of disease course, diagnostic criteria of MS and magnetic resonance imaging (MRI) protocols have changed multiple times, thus Hungarian MS centre conditions can be considered outdated.

Fig 1 — Black dots indicate the location of Hungarian MS care units. This map clearly represents that MS care unit density is highest in Pest County, where the capital city of Budapest with highest population density is located, whereas in other counties with less residents, usually 1 care unit/county is responsible for MS patient management. Abbreviations: MS = multiple sclerosis.

1.4. Standardizing management of persons with multiple sclerosis

Over the past 25 years several aspects of MS have changed. As previously mentioned, disease course classification [6–8], diagnostic criteria [9–12], magnetic resonance imaging guidelines [13,14], the therapeutic arsenal and recommendations have rapidly evolved. Currently, due to the extensive research of the last three decades, all courses of the disease can be treated with various DMTs and symptomatic treatments [15]. Due to the rapid evolution of MS knowledge, it is comprehensible that GPs and general neurologists without experience in the MS field are not able to keep abreast of brain-health focused care [16], thus there was an increasing need for standardizing MS clinical care. Therefore, the latest therapeutic guideline was developed by the European Committee for Treatment and Research in Multiple Sclerosis with the contribution of European Academy of Neurology (ECTRIMS/EAN) [17,18] in 2018. The first recommendation of that guideline was that DMTs should only be prescribed in multiple sclerosis care units (MSCU), since MSCUs have the appropriate infrastructure to ensure adequate administration of DMTs, treatment if adverse reactions occur and proper monitoring of people with MS and treatment response [17,18]. Subsequently, in 2019 MS care unit criteria [19], were also developed, in which personnel, instrumental, associate professional requirements of care units were defined (Table 2).

Table 2. Multiple sclerosis care unit recommendations.

Summary of the Multiple Sclerosis Care Unit criteria

1. Core of the MSCU is the person living with MS, MS neurologist, MS nurse and at least 3 of the following: pharmacist, neuropsychologist, speech therapist, dietitian, continence specialist, pain specialist, spasticity specialist (the latter 3 can be provided by the MS nurse or the MS specialist).
2. To ensure accurate diagnostics and differential diagnostics a qualified neuro-radiologist, microbiology, laboratory, electrophysiology and ophthalmology and an MRI device should also be accessible.
3. A fully developed MSCU should collaborate with many other neighbouring specialties as well: neuro-ophthalmologist, oto-neurologist, neurorehabilitation, neurosurgeon, surgeon, obstetrician-gynaecologist, internal medicine specialist, psychiatrist to treat complications and manage comorbidities.

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Abbreviations: MS = multiple sclerosis, MSCU = multiple sclerosis care unit.

1.5. Objectives

Since the creation of these guidelines [17–19], no survey was conducted to assess the real-world adaptation of these criteria. Hence, in 2019 the Danube Symposium for Neurological Sciences (DSNS) member countries decided to create the Multiple Sclerosis National Symposium, aiming to collect and assess data regarding inpatient and outpatient care of people with MS.

The present study is part of an international survey series conducted in DSNS member countries. Taking into account that such robust data collection is time and human resource demanding, data acquisition and analysis from DSNS member countries is in process. At the same time, considering the lack of similar assessments in the past, the present study can be considered as a pilot investigation aiming to collect data only from Hungarian MS care units, before presenting international outcomes. The main objective was to assess whether Hungarian MS care units fulfil international criteria. This objective could be divided into three subobjectives:

to assess Hungarian MS care units’ personnel and infrastructural equipment,
to enquire about DMT use
to determine number of persons living with MS receiving care in these units, and to compare these data to national prevalence estimates.

2. Materials and methods

2.1. Study design

The survey was conducted at the Department of Neurology University of Szeged, Albert Szent-Györgyi Health Centre, Szeged, Hungary with the contribution of Hungarian MS care units. The main goal of the survey was to assess personnel and infrastructural criteria of MS care units. Hence, a self-report questionnaire was assembled according to the ECTRIMS/EAN [17,18] and the MS care unit [19] guidelines at the beginning of November, 2020, and the end-date of data collection was January 31, 2021. The questionnaire consisted of 3 main sections: first section assessing personnel and instrumental equipment, second section examining DMTs used in the care unit, and the third section surveying number of people with MS receiving care at the MSCU (Tables 3 and 4). Resources on which the questionnaire was based, were attached to the main file, to minimize misunderstanding amongst colleagues. NHIF data were also gathered regarding DMT use of December 2020 to get a comprehensive overview on proportion of moderately and highly active therapy use in a national level.

Table 3. MS care unit criteria–first part of the questionnaire.

MS care unit criteria–detailed questionnaire
Minimum requirements of a multidisciplinary MS care unit	Occupied in the MS care unit
Core of the MS care unit
Number of persons with MS receiving care	_________
Number of MS neurologists	_________
MS nurse	☐ Yes / ☐ No
Secretary	☐ Yes / ☐ No
Collaboration with part-time specialists
Neuropsychologist	☐ Yes / ☐ No
Pharmacist with special knowledge of DMTs	☐ Yes / ☐ No
Dietitian	☐ Yes / ☐ No
Speech therapist	☐ Yes / ☐ No
Pain specialist	☐ Yes / ☐ No
Continence specialist	☐ Yes / ☐ No
Spasticity specialist	☐ Yes / ☐ No
Recommended requirements to achieve a fully developed multidisciplinary MS care unit	Occupied in the MS care unit
Collaboration with other specialties
Radiology with MS-familiar neuro-radiologist	☐ Yes / ☐ No
Physician	☐ Yes / ☐ No
Surgeon	☐ Yes / ☐ No
Neurosurgeon	☐ Yes / ☐ No
Obstetrician gynaecologist	☐ Yes / ☐ No
Neuro-ophthalmologist	☐ Yes / ☐ No
Neuro-otologist	☐ Yes / ☐ No
Psychiatrist	☐ Yes / ☐ No
Neurorehabilitation	☐ Yes / ☐ No

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Abbreviations: MS = multiple sclerosis.

Table 4. MS care unit criteria–second part of the questionnaire.

Currently used DMTs in the MS care unit
For low disease activity	For high disease activity	For very high disease activity	Other
☐ Interferon β	☐ Natalizumab	☐ Alemtuzumab	☐ Mitoxantrone
☐ Glatiramer acetate	☐ Fingolimod	☐ Ocrelizumab	☐ Azathioprine
☐ Dimethyl fumarate		☐ Cladribine	☐ Cyclophosphamide
☐ Teriflunomide			☐ Siponimod

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Abbreviations: DMT = disease modifying therapy.

2.2. Ethical approval

The study was approved by the Hungarian Medical Research Council, reference number: IV/5139-1/2021/EKU. The study was conducted in accordance with the Declaration of Helsinki.

2.3. Statistical analysis

Descriptive statistics were used to summarize data.

3. Results

3.1. Participation rate

The total number of respondents were 29 out of 31 care units, resulting in a 93.55% participation rate. However, only 24 care units provided information to every aspect of all sections of the questionnaire (Table 5). Yet, all 29 received questionnaires were included in the analysis, irrespective of being filled in partially or completely. To ensure anonymity, care units participating in the assessment were numbered consecutively from 1 to 29.

Table 5. Proportion of care units providing information on different aspects of the questionnaire.

Aspects	Proportion of MSCUs providing information
Personnel and instrumental background of the MSCU: Number of MS neurologist	26/29 (89.66%)
Personnel and instrumental background of the MSCU: MS nurse and secretary employment, neighbouring specialties, and diagnostics	27/29 (93.10%)
DMT use	27/29 (93.10%)
Number of MS patients	27/29 (93.10%)

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Abbreviations: DMT = disease modifying therapy, MS = multiple sclerosis, MSCU = multiple sclerosis care unit.

3.2. Care unit personnel and instrumental background

Regarding number of MS neurologist, 26 care units provided information, giving a total number of 86. The median number of MS neurologists was 3 (range, 1–8). When examining the rest of the MS care unit minimum and recommended requirements 27/29 care units provided information regarding personnel and infrastructural background. From the respondent care units 26 employed an MS nurse, and 21 employed a secretary. Concerning collaboration with other specialties, spasticity specialist (13/29), pain specialist (15/29), neuro-ophthalmologist (15/29) and oto-neurologist (15/29), neuropsychologist (19/29), speech therapist (21/29) were the least prevalent. Other required specialty missing was MS radiologist, absent in 3 care units, in 5 care units neurorehabilitation was not accessible and 2 care units did not own an MRI device. Summarizing the data 3/29 care units fulfilled only the minimum, 7/29 centres fulfilled both the minimum and recommended, while the remaining 17 centres did not fulfil all aspects of either minimum or recommended criteria and 2 care units did not provide information on personnel and infrastructural background (Fig 2).

Fig 2 — Respondent Hungarian MS care units are numbered from 1 to 29. In the first column MS care unit minimum and recommended criteria are listed. In the first 2 rows patient number receiving care at the care unit and number of MS neurologists are marked. At the bottom 4 rows summary of care units fulfilling all aspects of the minimum and recommended criteria are represented as well as number of unfulfilled criteria care unit by care unit. In the last column the number of care units out of all respondent care units fulfilling a criterion is summarised. “X” indicates that criterion is fulfilled. “N/A” indicates that no data were supplied. Abbreviations: MS = multiple sclerosis.

3.3. Disease modifying therapy use in care units

Concerning DMT use 27/29 care units provided information. In 27/29 care units all low efficacy DMTs were administered. Considering highly effective oral and infusion therapies there were differences among care units. In 20/29 care units all highly effective oral DMTs were used. From the remaining 7 care units 1 used only cladribine (CLA) and 5 used only fingolimod (FG) and 1 care unit did not use either FG or CLA. In 16/29 care units all highly effective infusion DMTs were used. From the remaining 11 care units 5 administered natalizumab (NAT) and ocrelizumab (OCR). In 1 care unit only NAT and alemtuzumab (ALM) was provided. In 1 care unit only OCR was administered, and in 1 care unit only ALM was used. In 3 care units neither of the highly effective infusion therapies were provided. However, there were only 15/29 care units, that administered all highly effective oral and infusion therapies, since in care unit no 7 CLA was not used, but the rest of the therapies were (Table 6).

Table 6. Disease modifying therapy use in care units.

	ß-IFN	DMF	GA	TFL	FG	CLA	NAT	ALM	OCR
1.	X	X	X	X	X	X	X	X	X
2.	X	X	X	X	X	X	X		X
3.	X	X	X	X	X	X	X	X	X
4.	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
5.	X	X	X	X	X	X	X	X	X
6.	X	X	X	X	X	X	X	X	X
7.	X	X	X	X	X		X	X	X
8.	X	X	X	X		X			X
9.	X	X	X	X	X	X	X	X	X
10.	X	X	X	X	X	X	X		X
11.	X	X	X	X	X	X	X	X	X
12.	X	X	X	X	X	X	X		X
13.	X	X	X	X	X	X	X	X	X
14.	X	X	X	X	X
15.	X	X	X	X	X	X	X	X	X
16.	X	X	X	X	X	X	X	X	X
17.	X	X	X	X	X	X	X	X	X
18.	X	X	X	X	X
19.	X	X	X	X	X	X	X	X	X
20.	X	X	X	X	X	X	X	X	X
21.	X	X	X	X	X
22.	X	X	X	X	X	X	X	X	X
23.	X	X	X	X	X		X		X
24.	X	X	X	X			X		X
25.	X	X	X	X	X	X		X
26.	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
27.	X	X	X	X	X	X	X	X	X
28.	X	X	X	X	X	X	X	X	X
29.	X	X	X	X	X	X	X	X

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In the first column respondent Hungarian Multiple sclerosis care units (numbered from 1 to 29) are listed, in the first row, abbreviations of disease modifying therapies’ active substances are listed.

“X” indicates that the disease modifying therapy is used in the care units, cell with a grey background indicates that the disease modifying therapy is not used in the care unit, “N/A” means that no data were supplied.

Abbreviations: ALM = alemtuzumab, ß-IFN = ß-interferon, CLA = cladribine, DMF = dimethyl fumarate, FG = fingolimod, GA = glatiramer acetate NAT = natalizumab, OCR = ocrelizumab, TFL = teriflunomide.

3.4. Proportion of moderately and highly effective disease modifying therapy use

According to the NHIF database 4665 people with MS received DMTs in December 2020, of which 3131 (67.12%) received low efficacy DMTs. Of these persons 1360 (43.44%) used injectable treatment and 1771 (56.56%) were on oral medication. The proportion of people on highly effective therapies was lower, 1534 (32.88%) persons received either highly effective oral or infusion therapy. Of these people 810 (52.80%) used oral agents, for example cladribine or fingolimod, and 724 (47.20%) were on infusion therapy e.g., alemtuzumab, natalizumab, ocrelizumab.

3.5. Number of persons living with multiple sclerosis receiving care in care units

Concerning number of people with MS, 27/29 care units provided information, in those care units 7213 persons received medical care. The median number of people living with MS receiving care was 240 (range, 40–950). The 4 University Departments, 2 county hospitals and 2 general hospitals of Budapest cared for more than 400 persons. In these 8 care units 3876 (53.74%) people received medical care. In 10 care units caring for 196–348 persons, 2483 (34.42%) people received care, whereas the remaining 9 care units were accountable for the medical care of 854 (11.84%) persons living with MS (Fig 3).

Fig 3 — In the linear axis respondent multiple sclerosis care units numbered from 1 to 29 are listed, in the perpendicular axis number of persons with multiple sclerosis receiving care is represented. “N/A” indicates that no data were supplied. Abbreviations: MS = multiple sclerosis.

4. Discussion

First objective of the study was to assess Hungarian MS care units’ personnel and infrastructural background. According to the assessment, only 3 care units qualified for minimum, and 7 care units acquitted to both minimum and recommended requirements. On one hand, the low proportion of care units fulfilling criteria suggests that there is plenty of space for improvement for MS care units in the future. This assessment established the most crucial elements of missing criteria, thus providing opportunity to ameliorate the conditions responsible for patients not receiving equal care. On the other hand, for an ordinary MS care unit these conditions might be too strict to fulfil. The least prevalent neighbouring specialties were spasticity and pain specialist, and neuro-ophthalmologist and oto-neurologist. Since these specialties are quite rare in general, it might be worthy to consider assigning regional care units employing these specialists, providing consulting hours for less equipped centres. Another feasible solution could be to incorporate smaller care units into larger ones, considering units caring for more people with MS, usually fulfil more criteria, thus provide better care. In 7 care units either the absence of a secretary or an MS nurse was the main reason for not fulfilling minimum criteria. Yet, care units only having insufficiencies in these aspects, could quickly increase MS nurse and secretary employment, since this is funded by the Hungarian Government.

As previously mentioned, no surveys were conducted to assess whether or how MS care unit criteria are fulfilled in real-world practice. However, these criteria were carefully reviewed from a different aspect by a panel of neurologists from Latin America [20]. In Latin America diagnosis and treatment of MS was usually carried out by general neurologists, and care of people with MS was not perused in specialized centres, thus the panel’s objective was to create a realistic adaptation of the MS care unit recommendations considering regional differences regarding healthcare in Latin American countries. Cristiano et al acknowledged the importance of MSCUs to optimize MS care and reached consensus on what a care unit in Latin America should offer. However, they also concluded, that despite the desire to meet the personnel and instrumental requirements of an MSCU, it would be difficult to implement these expectations in certain regions of Latin America. Thus, they determined a standardized protocol for MRI assessments and recommended education of general neurologists to facilitate accurate diagnosis and treatment of MS. At the same time, they also proposed the idea of close collaboration between general neurologists and MSCUs, and similarly to our assessment they propounded the feasibility of reference care units.

The current assessment’s second objective was to enquire about DMT use. According to the questionnaires, while all care units used the available low efficacy DMTs, only 15 care units administered all highly effective therapies as well, thus, in the rest of the care units, equality to access treatment might not be ensured. The reason behind this may be that highly effective infusion therapies might have severe side effects, such as natalizumab associated PML [21], alemtuzumab associated infusion reaction, infection and secondary autoimmune diseases [22], and ocrelizumab associated infusion reaction and infections [23]. Yet, a well-equipped MS care unit should be able to administer all DMTs and manage all side effects according to the ECTRIMS/EAN guideline [17,18]. Unlike in other countries, where not every DMT is available or funded by the health insurance, contributing to inequality [24,25], in Hungary all therapeutic options are funded by the NHIF, thus appropriate treatment of people with MS should be achievable, if adaptation to the latest guidelines came to fruition. The need for adaptation of the therapeutic guidelines was affirmed by other papers as well [26,27].

According to the NHIF database 4665 persons with MS received DMT in December 2020. However, the proportion of people with MS on DMT could not be established, since 4 care units did not provide data regarding the number of persons living with MS. Another deduction according to the NHIF data is that the use of oral DMTs is preferred in Hungary. Having said that, the proportion of people with MS on oral platform therapies could be higher, since administration is easier. On the flip side, the proportion of persons with MS on highly effective oral DMTs could be lower, since it might be assumed that, alemtuzumab and ocrelizumab decrease annual relapse rate and disease progression more effectively than fingolimod [28], even though head-to-head studies were not conducted. DMT use on a national level also suggests that in terms of therapeutic approach, escalation might still be favoured over induction. This approach may result in higher Expanded Disability Status Scale (EDSS) scores and disability, as well as lower quality of life eventually [29]. Furthermore, disability, fatigue and depression also result in lower working capacity, and unemployment raising indirect costs of MS [30].

Third objective of this survey was to determine number of people living with MS receiving care in Hungarian care units. According to our data collected from self-report questionnaires, 7213 persons with MS received medical care in 27/31 MS care units, from the remaining 4 care units 2 care units did not provide information regarding the number of people with MS, and 2 care units did not participate in our assessment at all. Considering proportion of participants, the assessment can be considered representative, since it covers approximately 90% of the Hungarian population living with MS. These results show a much lower number of persons living with MS than expected, according to two recently published epidemiological studies estimating prevalence of MS in Hungary, using different methods.

The more recent study [31] used the 10^th edition of the International Classification of Disease (ICD-10) and estimated the prevalence to be 130.8/100000. According to that estimate approximately 13000 persons with MS should live in Hungary, which would mean that almost 6000 people are “lost in the system”. However, in Hungary the ICD-10 system does not include itemized settlements of accounts, meaning the code G35H0 could stand for several diagnoses in diseases that cause demyelination of the CNS. Thus, this method could have probably resulted in an overestimate of the prevalence of MS. Furthermore, this technique might only be helpful in sorting out people diagnosed with MS, other characteristics of the disease, such as disease course, DMT use, EDSS scores, psychopathology are not accessible, concluded by other authors [32].

The other recent epidemiological study [33] was based on rigorous regional registry data of Csongrád-county [34], where 4% of the Hungarian population lives, thus it can be considered representative. According to that paper the standardised prevalence of MS was 101.8/100.000, meaning that approximately 10000 persons with MS should live in the country. This method is considered more reliable, since registries provide extensive real-world, up-to-date data regarding information on people living with MS, formerly used in countless well-known epidemiological studies [35–41]. However, even when comparing the current study’s number of persons living with MS to this estimate, a huge gap was discovered, meaning approximately 2500 people with MS are not receiving appropriate, MS specific medical care.

As previously mentioned, 2 care units did not participate in our assessment, and 2 participating centres did not provide information regarding number of persons living with MS, thus contributing to low number of people with MS. Another possible explanation behind this phenomenon could be that persons with MS after disease onset might not receive an accurate diagnosis, since misunderstanding and misapplication of the latest diagnostic criteria might still cause diagnostic problems among general neurologists and even among MS specialists [42,43], or if diagnosed with clinically isolated syndrome or RRMS correctly, people with MS might not attend doctor’s appointments due to low disease burden or because of the lack of awareness of illness. Another reason could be that people with progressive phenotype are often undertreated. On one hand, persons with PPMS usually present with initial symptoms involving the lower limb, such as paraparesis or weakness, thus being misdiagnosed as disc hernia or other rheumatoid or orthopaedic disorder of the lower extremity [44]. However, diagnosing people with PPMS in time should be prioritized, since there is a therapeutic option that slows disease progression significantly [23], yet it can only be prescribed for people with PPMS having an EDSS score below 5.5. This finding suggests that educating GPs and other associate specialties to recognise PPMS could resolve this problem. On the other hand, severely disabled persons living with SPMS or PPMS no longer attend doctor’s appointments because of their difficulty in mobility. Immobility is mainly caused by worsening spasticity and chronic pain thus appropriate management of these symptoms would be particularly important. However, according to our findings, spasticity and pain specialists are the least common neighbouring specialties in Hungarian MS care units, possibly contributing to low number of people living with MS and resulting in inequality in access to treatment.

Strengths of this study include, that this is the first assessment regarding the operation of MS care units in clinical practice, using the latest guidelines. Because of the high respondence rate this assessment can be considered representative, as it covers 93.55% of the Hungarian MS care units. Due to this assessment, we identified the aspects that should be improved upon to provide better healthcare and possibly better quality of life for people with MS, long term.

Limitation of this study is that the results of the self-report questionnaires only represent whether MS centres fulfil MS care unit’s minimum and recommended criteria. Yet it was not compared to patient reported outcome measures regarding satisfaction with quality of healthcare, since organising such an investigation is time and human resource consuming. The results could have been compared to patient information if Hungary owned a national multiple sclerosis registry. In addition to the absence of a national registry, 4 care units did not provide information regarding number of persons with MS, thus actual number of Hungarian people with MS could not have been determined, which also underlines the importance of creating and using a national MS registry. Another limitation of this survey is that it was conducted only in Hungary, thus it might seem that strictly national MS care units benefit from these results. Yet it could be the beginning of a survey series taking place in other countries, since being aware of the areas that need improvement would be beneficial for other health care system providers and receivers as well. In fact, this Hungarian survey is part of a bigger, more representative ongoing assessment in contribution with DSNS member countries.

5. Conclusion

In conclusion, according to our assessment to ensure equality to access treatment, more than half of the Hungarian MS care units might need improvements regarding personnel background and DMT use to meet all standards of the international guideline’s recommendation and to provide most professional care for persons living with MS. Furthermore, the Hungarian population of people with MS receiving medical care in MS care units is below estimated, because people with primary progressive phenotype are often misdiagnosed or undiagnosed. Thus, presumably educating GPs and neighbouring specialties might improve diagnosis of PPMS, and the symptomatic treatment of severely disabled persons with progressive phenotype may also improve number of people with MS. At the same time, to be able to establish actual number of persons living with MS, a national MS registry is still a necessity.

Acknowledgments

The authors thank the Danube Symposium for Neurological Sciences for collaboration.

The authors thank the Doctoral School of Clinical Medicine University of Szeged, Clinical and Experimental Neurosciences PhD program.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was funded via the University of Szeged in the form of independent grants to ZsK (5535 / EFOP 3.6.3-VEKOP-16-2017-00009) and LV (GINOP 2.3.2-15-2016-00034 / TUDFO/47138-1/2019-ITM). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

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PONE-D-21-33594Do Hungarian multiple sclerosis care units fulfil international criteria?PLOS ONE

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Additional Editor Comments:

Authors have raised some minor comments I would like you to address in the revision.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: • Figura 2: Line 230-240

"X": It should probably be the opposite, as an X or + means usually that the criteria is fulfilled

Non-fullfilled could be blank (or grey) or -

It would be more easily understandable (as X usually in this type of graphic means a positive answer)

• Table 6. Lines 253-256

Again here X probably should be changed by grey (as it is) or - and delete X

• Lines 265-270

Please provide apart from %, the number of patients in each case before (% in brackets)

• Lines 271-278

Same commentary than previous one - n(%)

• Discussion Lines 285-403

Probably the following article, at least should be mentioned in the discussion (and in the literature review), as I believe, is the only one that has treated the same topic, from other points of view, but complementary to this article.:

Cristiano E, Abad P, Becker J, Carrá A, Correale J, Flores J, Fruns M, Garcea O, Garcia Bónitto J, Gracia F, Hamuy F, Navas C, Patrucco L, Rivera V, Velazquez M, Rojas JI. Multiple sclerosis care units in Latin America: Consensus recommendations about its objectives and functioning implementation. J Neurol Sci. 2021 Oct 15;429:118072. doi: 10.1016/j.jns.2021.118072. Epub 2021 Sep 8. PMID: 34509134.

Reviewer #2: The present study’s objective was to assess whether Hungarian MS care units fulfil international criteria.

Overall the methodology and statistics use is appropriate

I would suggest to use disease modifying therapy instead of immunomodulatory therapies.

As well persons or people with MS instead of MS patients would be more appropriate term.

Authors should explain why only data from Hungary are reported, as they stated that “Danube Symposium for Neurological Sciences member countries decided to create the Multiple Sclerosis National Symposium, aiming to collect and assess data regarding inpatient and outpatient care of people with MS.”

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2022 Mar 3;17(3):e0264328. doi: 10.1371/journal.pone.0264328.r002

Author response to Decision Letter 0

21 Jan 2022

We are grateful for the quick response and the helpful recommendations.

Review comments made by the Reviewers:

Reviewer #1

1) Figure 2, lines 230-240

Figure 2 and legend of Figure 2 were changed according to the Reviewer’s observation, from:

“X indicates unfulfilled criterion, + indicates that all minimum and/or recommended criteria are met”

to:

“X indicates that criterion is met”

2) Table 6, lines 253-256

Table 6 and legend of Table 6 were altered pursuant to the Reviewer’s comment, from:

“� indicates that the disease modifying therapy is used in the care units, X with a grey background indicates that the disease modifying therapy is not used in the care unit, N/A with a grey background means that no data were supplied”

to:

“X indicates that the disease modifying therapy is used in the care units, cell with a grey background indicates that the disease modifying therapy is not used in the care unit, “N/A” means that no data were supplied.

3) Lines 265-270

Number of patients were added in each case, and percentages were placed into round brackets according to the Reviewer’s recommendation.

4) Lines 271-278

Number of patients were added in each case, and percentages were placed into round brackets in line with the Reviewer’s suggestion.

5) Discussion lines 285-403

The reference recommended by the Reviewer was added as a new paragraph to the Discussion Section:

“As previously mentioned, no surveys were conducted to assess whether or how MS care unit criteria are fulfilled in real-world practice. However, these criteria were carefully reviewed from a different aspect by a panel of neurologists from Latin America [20]. In Latin America diagnosis and treatment of MS was usually carried out by general neurologists, and care of people with MS was not perused in specialized centres, thus the panel’s objective was to create a realistic adaptation of the MS care unit recommendations considering regional differences regarding healthcare in Latin American countries. Cristiano et al acknowledged the importance of MSCUs to optimize MS care and reached consensus on what a care unit in Latin America should offer. However, they also concluded, that despite the desire to meet the personnel and instrumental requirements of an MSCU, it would be difficult to implement these expectations in certain regions of Latin America. Thus, they determined a standardized protocol for MRI assessments and recommended education of general neurologists to facilitate accurate diagnosis of MS. At the same time, they also proposed the idea of close collaboration between general neurologists and MSCUs, and similarly to our assessment they propounded the feasibility of reference care units.”

The reference recommended by the Reviewer was also added to the Reference Section:

“20. Cristiano E, Abad P, Becker J, Carrá A, Correale JF, Fruns M, et al. Multiple clerosis care in Latin America: Consensus recommendations about its objectives and functioning implemetation. J Neurol. Sci. 2021 Oct 14;429:118072. https://doi.org/10.1016/j.jns.2021.118072”

Reviewer #2

1) The expression “immune modulatory therapy” was switched to “disease modifying therapy” in the Introduction Section, according to the Reviewer’s advice.

2) The term “MS patients” was altered to either “persons with MS”, “persons living with MS” or “people with MS”, “people living with MS” throughout the manuscript, in line with the Reviewer’s proposition.

3) Explanation of “why only data from Hungary were reported” suggested by the Reviewer, was added at the end of the Introduction Section’s Objectives Subheading:

“The present study is part of an international survey series conducted in DSNS member countries. Taking into account that such robust data collection is time and human resource demanding, data acquisition and analysis from DSNS member countries is in process. At the same time, considering the lack of similar assessments in the past, the present study can be considered as a pilot investigation aiming to collect data only from Hungarian MS care units, before presenting international outcomes.”

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