Healthcare management of children with an acquired demyelinating syndrome in the Czech Republic

Summary

Aim: The aim of this study was to investigate the distribution and extent of healthcare provided to children with a suspected acquired demyelinating syndrome (including acute disseminated encephalomyelitis, clinically isolated syndrome, multiple sclerosis and neuromyelitis optica spectrum disorder) and to identify areas for care improvement in the Czech Republic. Patients and methodology: Electronic questionnaire survey at all inpatient departments of pediatric neurology (N = 7) and pediatric departments (N = 22) at the regional and university hospital level. Responses were obtained from all contacted hospitals. Results: All inpatient departments of pediatric neurology and 10 pediatric departments are involved in the care of patients. All have the necessary diagnostic methods available, but therapeutic options differ. We identified specific differences in the diagnostic approach  -in the indication and interpretation of examinations and in the use of current diagnostic criteria. In six regions, care is provided primarily by departments of pediatric neurology. In the remaining eight regions, patients are admitted to pediatric departments with an available pediatric neurology consultant. More complex cases are transferred to pediatric neurology departments, where the diagnostic approach is more comprehensive and the therapeutic options are more extensive. Conclusion: In the Czech Republic, healthcare for children with an acquired demyelinating syndrome is at a high level, but it is not standardized. The most appropriate standard of care is provided in specialized care centers for multiple sclerosis and neuromyelitis optica spectrum disorders. Given the distribution of care, specialized education must also include pediatricians and pediatric neurology consultants.

Keywords:

Pediatrics – Multiple sclerosis – Czech Republic – demyelinating autoimmune disorders – care management – tertiary care centers

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Inflammatory demyelinating diseases of the CNS are a heterogeneous group of rare diseases that can seriously affect a child's quality of life. Their common feature is the loss of myelin sheaths in the CNS due to a monophasic or relapsing autoimmune process. In the foreign literature, this group is represented by the term acquired demyelinating syndrome (ADS). Among the monophasic diseases, acute disseminated encephalomyelitis (ADEM) or various forms of clinically isolated syndrome (CIS), most often characterised by optic neuritis, inflammatory trunk involvement or acute myelitis, are encountered in childhood. In relapsing disease, MS, neuromyelitis optica spectrum disorder (NMOSD) and a recently defined group of diseases associated with myelin oligodendrocyte glycoprotein antibody-positive disease (MOGAD) are also encountered in childhood [1]. The overall incidence of ADS in children is estimated at 0.6-1.66 per 100,000 children/year based on isolated population-based studies [2-4]. Diagnosis is based on a combination of clinical and paraclinical examinations, their evolution over time, and exclusion of alternative etiologies (e.g., infection, metabolic defect, tumor, etc.) [5]. Diagnostic criteria for some ADS diseases in the paediatric population were established by consensus of an international expert working group in 2013 [6]. In 2015, the definition and diagnostic criteria for neuromyelitis optica (NMO) were expanded, and the new term NMOSD included a broader spectrum of manifestations, including forms without the presence of antibodies to aquaporin-4 (AQP4-IgG), in addition to optic neuritis and acute myelitis. The criteria have also been validated for the pediatric population [7,8]. For MS, the diagnostic criteria were last updated in 2017 [9]. Their utilization in children under 10 years of age is still a matter of debate.

Correct classification of the disease is essential for the choice of adequate therapy and the prognosis of the child. Low incidence in childhood, wide differential diagnosis, dynamic development of diagnostic criteria and therapeutic options may pose a challenge in routine clinical practice and limit the quality of care provided. Patients with MS and NMOSD in the Czech Republic are concentrated in centres of highly specialised care (CVSP), which offer an appropriate specialised multidisciplinary approach and modern therapy, especially for adults and, to a lesser extent, for children [10]. However, for other ADS diagnoses in children in the Czech Republic, a similar systemization of care is lacking and the parameters of established practice are unknown. The main aim of this study was to map the current management practices of paediatric patients with suspected ADS in the Czech Republic in comparison with international recommendations and to identify areas that offer scope for improving the care of children with ADS in the future.

 

Methodology

The basis was an electronic questionnaire survey in follow-up steps on two web-based platforms. Completion of information was done by correspondence or telephone. Primarily, we targeted the heads of all departments in the Czech Republic where we anticipated contact with ADS diseases due to the complexity of care. We contacted a total of 29 departments including all clinics and inpatient departments of paediatric neurology (n = 7) and large paediatric departments, most often at the level of regions and teaching hospitals (n = 22). The highest density of contacted departments was in Prague and the Central Bohemia Region.

The initial questionnaire was created in the GoogleForms platform (Google, Mountain View, CA, USA). Its purpose was to determine whether the diagnosis and acute treatment of the diseases under study (ADEM, some forms of CIS, RS, NMOSD, and MOGAD), patient translation practices, availability of a pediatric neurology consultant (for pediatric patients), and willingness to further collaborate were ongoing at the site. We approached all selected centres. If a hospital had both a child neurology (DN) and pediatrics department, we contacted both leaders at the same time. Feedback was generally provided by DN representatives. We obtained responses from all hospitals contacted.

The follow-up (methodological) questionnaire was developed in the REDCap platform (Vanderbilt University, Nashville, TN, USA). Its purpose was to obtain details of the management of patients with the diagnoses under study. The first set of questions targeted logistics (where patients with ADS come from and the distribution of their care in the hospital). The second heading concerned diagnosis (usual procedures, use of diagnostic criteria and availability of selected tests). The third track focused on follow-up care (clinical and laboratory follow-up, status of collaboration with catchment CVSPs for MS and NMOSD). This questionnaire was sent only to sites involved in diagnosis and treatment (n = 17), and two paediatric sites did not provide information.

 

Results

Children with suspected ADS come to the pediatric neurology and pediatrics departments

The initial questionnaire showed that children with suspected ADS come to all the contacted centres in all regions. In only six counties do these patients primarily receive diagnostic and therapeutic care directly at the DN bedside. In eight regions, patients are under the care of paediatricians at the regional hospital and a paediatric neurologist is available on a consultative basis. The situation in Prague and the Central Bohemia Region is unique because of the high density of paediatrics and the availability of DN beds in the three Prague teaching hospitals. One paediatric department in Prague and the Central Bohemian Region has always admitted a share in the care of patients with possible ADS. Diagnosis of at least one form of ADS is carried out at a total of ten paediatric and all seven DN departments. An overview of the hospitals contacted is shown in Figure 1

 

Children with severe ADS are transferred to the paediatric neurology unit

A follow-up methodology form was provided by all seven inpatient DN sites and eight of the ten paediatric sites involved in the care of children with some form of ADS. In summary, we obtained data on care from all regions; only two regions (Karlovy Vary and Liberec) had incomplete information.

Children with suspected ADS are seen in acute outpatient clinics, and most participating regional paediatric clinics also admit children on referral from outpatient paediatric neurologists; in the South Bohemia, Olomouc, Pardubice and Ústí nad Labem regions, children with neurological problems are admitted by transfer from adjacent district hospitals. Inpatient DNs admit children in all ways, including transfer from hospitals in other regions. An exception is the inpatient DN department at the General University Hospital in Prague, which usually provides only the necessary acute care for ADS patients and then translates them.

The full diagnostic and therapeutic care for children with ADS is therefore provided by six of the seven paediatric neurology departments, which cooperate with the paediatric, anaesthesiology and resuscitation (or other) department in the hospital as needed. A further seven of the ten participating paediatric departments are involved in the treatment of some diagnoses. All of these paediatrics generally transfer patients to DN beds when more complex diagnostic procedures or therapies (especially plasmapheresis and administration of biological therapy) are required. The most frequently mentioned translation destinations were the University Hospital Brno, the University Hospital Hradec Kralove, the University Hospital Motol and the University Hospital Thomayer.

 

The differential diagnosis of ADS is more detailed in the departments of paediatric neurology

Estimated numbers of patients with any form of ADS were highest in the clinics of DN University Hospitals (Brno, Motol, Ostrava, University Thomayer Hospital) and the Department of Child Neurology in Hradec Králové, ranging from 5-20 patients/year. Others estimated the number of patients in units of (less than five) cases/year. All 15 participating departments stated that they diagnose ADEM and MS. Six of eight pediatricians (vs. seven of seven DNs) used the latter diagnostic criteria for RS and four of eight pediatricians (vs. six of seven DNs) used the former for ADEM. A proportion reported a major contribution of the radiologist's opinion in making the diagnosis. More detailed diagnosis is completed by 14 sites for CIS and 13 sites for NMOSD. Five of the six diagnosing paediatrics and seven of the seven DNs use the most recent diagnostic criteria for NMOSD.

From the point of view of laboratory methods, the greatest consensus in the diagnosis of individual forms of ADS was in the indication of brain MRI and lumbar puncture with isoelectric focusing (IEF). All sites have instruments with a magnetic field strength of at least 1.5 T, with eight of the 15 having a 3 T instrument.

For the clinical manifestations of optic neuritis and acute myelitis, we asked whether normal initial MRI findings and/or absence of pleocytosis in the lymph exclude an inflammatory etiology. Most of the interviewees (except one pediatrician) admitted that normal findings on MRI do not exclude optic neuritis. In contrast, two of the seven DNs and four of the eight pediatricians incorrectly stated that normal spinal cord admission MRI ruled out acute myelitis. One paediatric department considered the absence of pleocytosis to be incompatible with acute myelitis; for optic neuritis, five departments considered a similar interpretation (in the context of other investigations).

There were also different responses to spinal cord MR supplementation in case of clinical brain (or optic nerve) involvement and to brain MR supplementation in case of clinical spinal cord involvement. These additional examinations are performed in between 64-93% depending on the diagnosis, regardless of the type of department. Contrast agent administration occurs only between 60-80% depending on the diagnosis being examined, and usually in children examined in DN beds. An overview of the routinely indicated examinations for each diagnosis with respect to the type of department is summarised in more detail in Table 2.

When evaluating the investigation of autoantibodies associated with ADS (MOG-IgG, AQP4-IgG), we found that AQP4-IgG was more frequently indicated than MOG-IgG. Depending on the diagnosis, the indication of AQP4-IgG ranged between 60-100% and MOG-IgG between 60-92%, and was more frequent in DN beds. Further broader immunological investigation was reported by 57-71% of sites and was again more common in DN beds. Detailed microbiological investigations were routinely performed by 73-79% of units.

The use of electrophysiological methods in diagnosis was significantly dependent on the form of ADS. All departments investigate visual evoked potentials in optic neuritis; in other diagnoses, their investigation ranges from 53-92% (least in ADEM, most in NMOSD), more often at DN beds. EEG is part of the diagnostic procedure in ADEM in only six of seven DN and four of eight paediatrics. Performing somatosensory evoked potentials as part of the diagnosis of acute myelitis was reported by five of seven DNs and one of eight paediatrics.

Visual functions are determined by all departments for optic neuritis and NMOSD, while for the remaining diagnoses their examination ranges between 57-73%. Depending on the diagnosis, optical coherence tomography (OCT) is performed in ADS in 35-86% of departments (least in acute myelitis, most in optic neuritis), more frequently in DN beds.

 

Dispensing children after the first episode of ADS is common in paediatric neurology

After an acute episode of ADS has been managed, patients remain in follow-up within all DN units that treat these children. Often they have a direct link to the CVSP for MS and NMOSD and then benefit from counselling in uncertain situations. Five of the eight paediatric units retain at least some of their ADS patients in follow-up. Children with MS or NMOSD are usually referred to catchment CVSPs with paediatric authorisation, and possibly to non-catchment CVSPs depending on age. Most of the affected centres (with the exception of one) provide follow-up MR imaging depending on the specific form of ADS. All acknowledged that surveillance imaging rarely leads to a change in the original diagnosis.

 

Discussion

Our work mapped the current situation of care for children with rare neurological diagnoses from the group of ADS diseases in the Czech Republic. We contacted all key centres and thanks to their willingness we obtained the necessary data.

The main finding was that children with ADS are distributed throughout the country and that acute and chronic care varies. There are differences in patient numbers, diagnostic approach and treatment options between different departments, especially between DN and paediatricians at regional level. Estimated numbers of patients per year are expected to be higher in inpatient DN, which is consistent with the experience of acute and follow-up care. However, up to a third of paediatric ADS cases are managed off-site by DNs at individual paediatric beds in collaboration with a neurological consultant. This shows the substantial involvement of higher paediatric departments in the care of children with ADS, even though it is a marginal diagnosis for them. It should be noted that accurate epidemiological data are still lacking and that data cannot be directly confused with the quality of care provided. Given the low incidence and the nature of ADS, high professional demands are placed on all those involved. For complicated cases, paediatric units take advantage of the possibility of transfer to DN beds, where the diagnostic approach is usually more up-to-date, comprehensive and the therapeutic options more extensive.

Our work has also shown specific differences in the use of current diagnostic criteria. Somewhat surprising was the small expansion of the ADEM criteria by Krupp et al. in 2013 [6]. Especially pediatric departments often rely only on the opinion of radiologists and do not supplement the EEG in the diagnosis. This may lead to the omission of encephalopathy as a necessary criterion in the reasoning and to an erroneous conclusion. In contrast, knowledge of the diagnostic criteria for NMOSD [7] and MS [9] has generally been widespread.

The availability of testing modalities necessary for the diagnosis of ADS is good in the Czech Republic. All workplaces have high quality MR equipment. The standard MR examination is 1.5 T. The possibility of using 3 T is also widespread, which brings higher sensitivity in the detection of demyelinating foci [11]. We have observed discrepancies in the indication of the extent of MR examination and its performance. In particular, contrast administration has been neglected, although current contrast agents have a favorable safety profile and tend to be well tolerated [12,13]. According to recommendations, the first diagnostic imaging when ADS disease is suspected should include the brain and the whole spinal cord with contrast agent administration [14]. Some foci of demyelination may be clinically mute but have diagnostic and prognostic significance [15,16]. The administration of contrast in the case of multiple lesions allows to distinguish their different ages (according to the presence of saturation), to assess the degree of inflammatory process in solitary foci and possibly to guide the consideration of a non-inflammatory etiology [17,18]. Repeating MRI to add contrast places an additional burden on the child (especially when general anesthesia is required) and slows the diagnostic process. Therefore, it is optimal to perform the first imaging with all the essentials already in place. However, repeat MR may be appropriate when negative findings are present at the onset of acute difficulties and persistence of a severe clinical condition. New signal changes or atrophy may be picked up within 5-7 days [19,20]. Mute initial MR findings with later development of atrophy have been described in optic neuritis and myelitis [21,22]. It is also recommended to use a standardized protocol to monitor the development of focal changes [18].

In the diagnosis of ADS in the Czech Republic, liquidus testing including oligoclonal banding is routinely performed. However, the measurement of MOG-IgG antibodies in serum, which is supposed to be the standard in paediatric ADS, has proved controversial. It is reported that up to 30% of ADS in childhood is associated with MOG-IgG antibodies [23]. Moreover, their determination has prognostic significance [24,25]. In contrast, the currently more frequently investigated AQP4-IgGs are generally, and in children in particular, very rare [26]. In the context of differential diagnosis, it is also advisable to think about the exclusion of systemic autoimmune diseases by immunological testing in individual cases, but this is overlooked in some departments [27]. The situation is similar with microbiological examination.

Recently, functional and structural examination of the optic nerves has been increasingly discussed in various forms of ADS. Their subclinical impairments may be revealed by visual evoked potentials or OCT, while visual examination and MRI images may still (or again) be normal [28]. Determination of subclinical optic nerve involvement and subsequent monitoring of its functional recovery may represent a diagnostic and prognostic biomarker in the future [29,30].

We believe that the differences in approach between DN and paediatrics are due to the nature of the two different disciplines and the limitations of experience with rare diagnoses. The differences cannot be primarily attributed to the unavailability of investigative methods; instrumentation and laboratory capabilities are sufficient in most hospitals. The problem remains their timely indication and correct interpretation. Our work shows that there is room for improvement of knowledge regarding diagnostic approaches and standardisation of care for children with ADS across neurological and paediatric departments in the Czech Republic. Given the distribution of care, future education must also focus on paediatric units, their consultant paediatric neurologists and with the collaboration of the CVSP for MS and NMOSD.

 

Conclusion

The care of children with ADS is at a high level in the Czech Republic, but it is not standardised for some diagnoses. MS and NMOSD seem to be the best provided for, for which there are CVSPs also dedicated to children. However, there is still a significant group of patients with other ADS conditions whose needs may be neglected.

 

Acknowledgements

We thank all our collaborators for their efforts to improve care for children with CNS demyelinating diseases.

 

Ethical aspects

The study is not subject to ethics committee approval.

 

Financial support

The work was supported by the grant No. 405822 of the Charles University.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the work presented.

 

Table 1. Acquired demyelinating syndrome -⁠ overview of diagnoses.

Monophasic		Recurrent/chronic
ADEM		RS
CIS	Optic neuritis	MOGAD
	transverse myelitis	NMOSD
	Stem syndrome	MDEM
	cerebellar syndrome	ADEM-ON
	hemispheric syndrome	RON

ADEM, acute disseminated encephalomyelitis; ADEM-ON, ADEM followed by recurrent optic neuritis; CIS, clinically isolated syndrome; MDEM, multiphasic ADEM; MOGAD, myelin oligodendrocyte glycoprotein antibody-associated disease; NMOSD, neuromyelitis optica spectrum disorder; RON, recurrent optic neuritis

Table 2. Overview of examinations performed in the diagnosis of ADS by type of department.

"-" -⁠ the question was not part of the questionnaire; * -⁠ always performed regardless of the presence of corresponding symptoms; highlighted fields -⁠ examination is performed by all diagnostic departments

ADEM -⁠ acute disseminated encephalomyelitis; AQP4-IgG -⁠ antibodies to aquaporin 4; AM -⁠ acute myelitis; DE -⁠ other monophasic demyelinating episode; Dg. criteria -⁠ utilization of current diagnostic criteria; IEF -⁠ isoelectrofocusing i.e. determination of oligoclonal bands; Immuno. -⁠ immunological sampling; LP -⁠ lumbar puncture; Micro. -⁠ detailed microbiological examination; MOG-IgG -⁠ antibodies to myelin oligodendrocyte glycoprotein; MRI with KL -⁠ MRI with contrast agent administration; N -⁠ paediatric neurological department; NMOSD -⁠ neuromyelitis optica spectrum disease; OCT -⁠ optical coherence tomography; ON -⁠ optic neuritis;P -⁠ paediatric department; Number of dg. -⁠ number of departments making a given diagnosis; SEP -⁠ somatosensory evoked potentials; VEP -⁠ visual evoked potentials

 

					CNS imaging						Liquor				Blood draws								Eye examination						Electrophysiology
Examinations / Diagnoses	Number of dg.		Dg. criteria		MRI of the brain*		MRI of the spinal cord*		MR with KL		LP		IEF		MOG-IgG		AQP4-IgG		Immune.		Micro.		Eye background		All		OCT		VEP		SEP		EEG
Workplace:	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P	N	P
ADEM	7	8	6	4	7	8	4	6	7	2	7	8	7	8	7	4	-	-	-	-	6	5	7	7	-	-	-	-	6	2	-	-	6	4
ON	7	7	-	-	7	7	4	5	6	3	7	7	7	7	7	4	7	7	5	3	6	4	7	7	7	7	6	6	7	7	-	-	-	-
AM	7	7	-	-	6	7	7	7	7	4	7	6	7	6	6	5	6	3	6	3	6	4	5	6	5	3	4	1	6	3	5	1	-	-
DE	7	7	-	-	7	7	5	6	7	4	7	7	7	7	7	5	7	5	6	4	6	5	5	7	5	5	4	3	7	4	-	-	-	-
RS	7	8	7	6	7	8	6	7	7	5	7	8	7	8	5	4	4	5	4	5	6	5	5	8	5	6	5	3	6	5	-	-	-	-
NMOSD	7	6	7	5	7	6	7	5	6	3	7	6	7	6	7	5	7	6	5	4	6	4	7	6	7	6	6	5	7	5	-	-	-	-