1. Diagnostic algorithm for relapsing demyelinating syndromes (RDS) of the CNS in children
Yael Hacohen, Kshitij Mankad, W. Kling Chong, Frederik Barkhof, Angela Vincent, Ming Lim, Evangeline Wassmer, Olga Ciccarelli,
Cheryl Hemingway

2. Acute/Inflammatory demyelination syndrome/event
Multiphasic
ADEM
Relapsing NMO/ NMOSD
Multiple sclerosis
clinically
isolated syndrome
Identifying patients early
By contrast to adults most of the patients do not have MS
Research into clinical and radiological parameters of MS at first clinical presentation
ADEM is usually a monophasic disease that develops after vaccination or infection, predominantly in children
Other Relapsing:
Antibody mediated; ADEMON; CRION
Banwell et al., 2007 Lancet Neurology 6:
Krupp et al., 2013 Mult Scler. 19(10): 2

3. NMO called MS PHENOTYPES
Banwell et al. Lancet neurology 2007;10:

4. A nationwide survey of pediatric ADS in Japan
Yamaguchi et al. Neurology. 2016;87(19):

5. Aims Evaluate retrospectively a large cohort of children with RDS
Clinical assessments
Neuroimaging
CSF OCBs, serum AQP4+MOG-Abs, and EBV serology
Establish the key features that could lead to better definitions of each phenotype.
Develop a diagnostic algorithm that indicates the sequential diagnostic tests

6. Methods

7. Participants and study design
A 110 children with relapsing demyelinating syndromes
Consecutive children, who attended for follow-up identified from the clinical records.
All investigations were done for routine diagnosis

8. Clinical review and diagnosis
Cases were assigned to the following diagnostic categories: MS
NMOSD
MDEM and ADEM-ON
Recurrent demyelination in a single CNS area without evidence of clinically-silent disease (for example RION)

9. Blinded radiological analysis
Juxtacortical
Spinal Cord
Infratentorial
Periventricular
Analysis was repeated separately for baseline and follow-up scans.
MRI scans were given a category between 1-4;
1 = not MS
2 = not typical of MS,
3 = some MS features,
4 = typical of MS.
which aimed to assess whether imaging characteristics alone can support the diagnosis of specific RDS, without knowing the clinical features and the antibody results
In cases of scores 1 and 2
(i) disease localised to brainstem and hypothalamus;
(ii) predominantly confluent, hazy/poorly marginated lesions involving both grey matter and white matter;
(iii) extensive confluent ‘leukodystrophy-like’ MRI pattern;
(iv) sharply demarcated hemispheric white matter lesions (>3cm);
(v) TM and/or ON with normal intracranial appearance or non-specific white matter lesions.
11 locations: Diencephalon, Dorsal brainstem, Periependimal area surrounding the lateral ventricles, LETM, Cortical grey matter, Thalamus, Basal ganglia, Juxtacortical and deep white mater involvement more than periventricular, Cerebellar peduncles, Pons and ON/optic tracts
If scans were scored 3 and 4
MAGNIMS recommended MRI DIS criteria for the diagnosis of MS3 were counted .

10. Results

11. Demographics, clinical and paraclinical features of children according to their standard RDS diagnosis

13. Autoantibodies in non-MS phenotypes
34/41 (82.9%) patients with RDS other than MS were positive for either AQP4-Abs or MOG-Abs
30.7% (8/26) of NMOSD cases tested were AQP4-Ab-positive
83.3% (15/18) of AQP4-Ab negative NMOSD cases were MOG-Ab positive
No patients had Abs to both antigens
MOG-Abs were found in 100% (9/9) of MDEM tested cases and 33.3% (2/6) of RION tested cases

14. AQP4 vs MOG

15. AQP4 vs MOG

16. Blinded radiological analysis

17. AQP4 vs MOG MRI patterns
Disease restricted to the brainstem and/or hypothalamus
Destructive lesions
Dorsal brainstem
Cerebellar peduncles were only seen in the MOG-positive patients at both time points
at onset 38% vs 0%, p , and at follow-up 50% vs 0%, p ).

18. First (or subsequent) episode of central nervous system demyelination
Diagnose Multiple Sclerosis if McDonald criteria are met
MRI brain and spinal cord
Typical of “adult” multiple sclerosis
YES NO
Diagnose AQP4-Ab associated disease (NMOSD with AQP4-Abs)
Features of NMOSD
YES
Check AQP-4 antibody
+ve NO
-ve
Diagnose MOG-Ab associated disease
YES
Check MOG antibody
Features of ADEM
+ve
We proposed a diagnostic algorithm applicable to any episode of CNS demyelination, which leads to four main RDS: MS, NMOSD with APQ4-Abs, MOG-Abs associated disease, and Abs-negative RDS.
The first recommended diagnostic test is brain and spinal cord MRI. If MRI features considered to be typical of adult MS are seen, then the MS diagnostic criteria should be applied.
In children whose MRI is not typical of MS, then clinical and radiological features suggestive of NMOSD should be looked for, and if present, then AQP4-Ab testing is recommended. In particular, this test is advised in children presenting with an area postrema syndrome, MRI abnormalities localized to the brainstem and hypothalamus, and destructive lesions at follow-up. If AQP4-Abs are negative, then MOG-Abs should be tested.
In children whose MRI is not typical of MS and NMOSD, but the clinical and radiological presentation has features of ADEM, MOG-Ab testing is recommended. In particular, this test is advised in children who show a lesion in the cerebellar peduncle.
Consideration of alternative diagnoses and monitoring are recommended in Abs-negative RDS, who are the minority of RDS cases. NO
-ve
MONITOR
Antibody negative relapsing demyelinating syndrome
Consider alternative diagnoses
RELAPSE

19. Conclusion
MRI separates between MS and the other demyelinating phenotypes
No differences were identified when comparing MS children presenting <12yrs than over
Nearly half of the children clearly had non-MS phenotypes
Since MOG-Abs positive patients showed clinical and MRI features different from MS and NMOSD with AQP4-Ab, they should be grouped into a unified phenotype

20. Kshitij Mankad
W. Kling Chong
Frederik Barkhof
Angela Vincent
Ming Lim
Evangeline Wassmer
Olga Ciccarelli
Cheryl Hemingway
UK-CID