Differential diagnosis of demyelinating diseases: what's new?

Diagnóstico diferencial das doenças desmielinizantes: o que há de novo?

Ana Beatriz Ayroza Galvão Ribeiro Gomes Tarso Adoni About the authors

ABSTRACT

Background:

Acquired demyelinating disorders lead to overlapping visual, pyramidal, sensory, autonomic, and cerebellar deficits and may lead to severe disability. Early diagnosis and start of treatment are fundamental towards preventing further attacks and halting disability.

Objective:

In this paper we provide an updated overview of the differential diagnoses of acquired demyelinating disorders.

Methods:

We performed a critical targeted review of the diagnoses of the most prevalent demyelinating disorders: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

Results:

We discuss the workup, diagnostic criteria and new biomarkers currently being used for the diagnosis of these disease entities taking into account the particularities of the Brazilian population and healthcare system.

Conclusion:

A comprehensive analysis of medical history, physical examination, biomedical and imaging data should be performed to obtain differential diagnosis. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.

Keywords:
Multiple Sclerosis; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Diagnosis

RESUMO

Antecedentes:

Doenças desmielinizantes adquiridas levam a déficits visuais, piramidais, sensitivos, autonômicos e cerebelares que se sobrepõem e podem conduzir a grave incapacidade. O diagnóstico e o início de tratamento precoces são fundamentais para a prevenção de surtos e ocorrência de incapacidade.

Objetivo:

Neste artigo, apresentamos uma visão geral atualizada sobre o diagnóstico diferencial de doenças desmielinizantes adquiridas.

Métodos:

Realizamos uma revisão crítica sobre o diagnóstico das doenças desmielinizantes mais prevalentes: esclerose múltipla (EM), doença do espectro neuromielite óptica (NMOSD) e doença associada ao anticorpo contra a glicoproteína da mielina do oligodendrócito (MOGAD).

Resultados:

Discutimos a investigação, os critérios diagnósticos e os novos biomarcadores atualmente empregados para o diagnóstico dessas doenças, levando em conta as particularidades da população e sistema de saúde brasileiros.

Conclusão:

Uma análise minuciosa do histórico médico, exame neurológico e exames biomédicos e de imagem deve ser realizada para se fazer um diagnóstico diferencial de doença desmielinizante. Critérios diagnósticos devem ser empregados cautelosamente considerando-se particularidades étnicas e ambientais de cada paciente.

Palavras-chave:
Esclerose Múltipla; Neuromielite Óptica; Glicoproteína Mielina-Oligodendrócito; Diagnóstico

INTRODUCTION

Acquired demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) compromise the optic nerves, brain and spinal cord and lead to a range of clinical symptoms including visual, pyramidal, sensory, autonomic, and cerebellar deficits. The diseases affect mainly young individuals and may lead to severe disability. In fact, MS is the second leading cause of disability of young adults in developed countries11. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010 May;9(5):520-32. https://doi.org/10.1016/S1474-4422(10)70064-8
https://doi.org/10.1016/S1474-4422(10)70...
.

Prompt diagnosis and initiation of treatment are essential towards preventing attacks and halting the accumulation of disabilities. The ability to perform accurate differential diagnoses is crucial to the good prognosis of patients, however it can be extremely challenging, as the field is dynamic and expanding, different disease entities clinically overlap and access to specific assays is still limited in certain settings.

This paper aims to provide an updated practical approach on how to perform the differential diagnoses of suspected acquired demyelinating syndromes taking into account the particularities of the Brazilian population and healthcare system.

METHODS

We performed a targeted literature review pertaining to the diagnosis of MS, NMOSD and MOGAD. Resulting evidence was jointly critically appraised by a junior and a senior neuroimmunologist.

Epidemiological/demographic update: prevalence of ADS in Brazil

Estimating the prevalence of demyelinating disorders in Brazil is challenging due to the absence of representative country-wide prevalence studies, heterogeneous access to qualified health systems and the ethnically diverse population. Nonetheless, a metanalysis described a national MS prevalence of 8.69/100,000 (95% CI: 6.0-12.6), with an association between the prevalence of MS and latitude of study location (OR=1.09; 95% CI: 1.04-1.14), ethnic composition (OR=1.03; 95% CI: 1.01-1.05) and weather. The authors identified a 9% increase in the prevalence rate of MS for the increase of each degree in latitude and a 3% raise in the prevalence of MS for every degree increase in the proportion of white people22. Pereira ABCNG, Lacativa MCS, Pereira FFCC, Alvarenga RMP. Prevalence of multiple sclerosis in Brazil: a systematic review. Mult Scler Relat Disord. 2015 Nov 1;4(6):572-9. https://doi.org/10.1016/j.msard.2015.08.004
https://doi.org/10.1016/j.msard.2015.08....
.

The prevalence of NMOSD is also heterogeneous and influenced by the population’s ethnical background. Different studies report prevalences in Brazil that range from 0.37 to 4.52/100,000 inhabitants with a north-south gradient decrease in the risk of developing NMOSD33. Alvarenga MP, Schimidt S, Alvarenga RP. Epidemiology of neuromyelitis optica in Latin America. Mult Scler J Exp Transl Clin. 2017 Sep 25;3(3):2055217317730098. https://doi.org/10.1177/2055217317730098
https://doi.org/10.1177/2055217317730098...
,44. Lana-Peixoto MA, Talim NC, Pedrosa D, Macedo JM, Santiago-Amaral J. Prevalence of neuromyelitis optica spectrum disorder in Belo Horizonte, Southeast Brazil. Mult Scler Relat Disord. 2021 May 1;50:102807. https://doi.org/10.1016/j.msard.2021.102807
https://doi.org/10.1016/j.msard.2021.102...
. Prevalence and disease phenotypes are influenced by ethnicity, and worse clinical outcomes are associated with Asian, African and Latin American ancestry55. Pandit L, Asgari N, Apiwattanakul M, Palace J, Paul F, Leite MI, et al. Demographic and clinical features of neuromyelitis optica: a review. Mult Scler. 2015 Jun 1;21(7):845-53. https://doi.org/10.1177/1352458515572406
https://doi.org/10.1177/1352458515572406...
.

MOGAD incidence rates worldwide range from 0.16 to 1.4 per 100,00066. Hegen H, Reindl M. Recent developments in MOG-IgG associated neurological disorders. Ther Adv Neurol Disord. 2020 Jul 31;13:1756286420945135. https://doi.org/10.1177/1756286420945135
https://doi.org/10.1177/1756286420945135...
. The proportion of MOG-IgG related acquired demyelinating syndromes (ADS) decreases with age. Higher disease incidences have been reported in pediatric cohorts (39%), than among mixed cohorts of children and adults (29%) or adults (23%)66. Hegen H, Reindl M. Recent developments in MOG-IgG associated neurological disorders. Ther Adv Neurol Disord. 2020 Jul 31;13:1756286420945135. https://doi.org/10.1177/1756286420945135
https://doi.org/10.1177/1756286420945135...
. Ethnicity initially seemed to not be as important with 78-90% (MOGAD) versus 60-63% (NMOSD) of Caucasians, however Brazilian data suggests that it may play a role in the prevalence of the disease77. Dos Passos GR, Oliveira LM, Costa BK, Apostolos-Pereira SL, Callegaro D, Fujihara K, et al. MOG-IgG-Associated optic neuritis, encephalitis, and myelitis: lessons learned from neuromyelitis optica spectrum disorder. Front Neurol. 2018 Apr 4;9:217. https://doi.org/10.3389/fneur.2018.00217
https://doi.org/10.3389/fneur.2018.00217...
,88. Papais-Alvarenga RM, Neri VC, Araújo ACRA, Silva EB, Alvarenga MP, Pereira ABCNG, et al. Lower frequency of antibodies to MOG in Brazilian patients with demyelinating diseases: an ethnicity influence? Mult Scler Relat Disord. 2018 Oct 1;25:P87-94. https://doi.org/10.1016/j.msard.2018.07.026
https://doi.org/10.1016/j.msard.2018.07....
. The nationwide estimations of the prevalence of MOGAD have not yet been published.

Diagnosis of demyelinating disorders

Demyelinating disorders lead to overlapping clinical syndromes. A methodical diagnostic approach, including thorough investigation of the medical history, neurological examination and complementary tests is helpful towards performing differential diagnoses (Table 1). Unfortunately, not all tests are available in the Brazilian public health system, therefore mindful investigation is suggested to prevent unnecessary financial expenses.

Table 1.
Diagnostic workup for demyelinating disorders.

The diagnoses can be obtained through the interpretation of the medical history, neurological examination, biomedical/imaging tests and application of current diagnostic criteria99. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb 1;17(2):P162-73. https://doi.org/10.1016/S1474-4422(17)30470-2
https://doi.org/10.1016/S1474-4422(17)30...
,1010. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. https://doi.org/10.1212/WNL.0000000000001729
https://doi.org/10.1212/WNL.000000000000...
(Tables 2, 3 and 4).

Table 2.
Diagnostic criteria for relapsing remitting multiple sclerosis.

Table 3.
Diagnostic criteria for primary progressive multiple sclerosis.

Table 4.
Diagnostic criteria for neuromyelitis optica spectrum disorders.

To this day, the diagnosis of MOGAD still relies on the identification of the MOG-IgG antibody in serum. Live cell-based assays are the established gold standard for the identification of the antibody, due to its superior sensitivity and specificity1111. Yeh EA, Nakashima I. Live-cell based assays are the gold standard for anti-MOG-Ab testing. Neurology. 2019 Mar 12;92(11):501-2. https://doi.org/10.1212/WNL.0000000000007077
https://doi.org/10.1212/WNL.000000000000...
. Unlike what is observed in MS and NMOSD, a portion of patients with MOGAD present with monophasic disease and therefore, might have a MOG IgG serostatus switch over time regardless of immunosuppressive treatment. The final diagnosis of MOGAD should account for the medical history and clinical phenotype of the patient in addition to their serostatus, as a percentage of patients with MS may present with low titers of MOG-IgG, while employed assays may not be adequately sensitive to detect low antibody titers and clear diagnostic criteria for the disease have not yet been defined.

Differential diagnosis

The careful interpretation of medical history, physical examination and additional investigation allows the distinction between the various acquired demyelinating syndromes (Table 5). It is important to highlight that the criteria currently used for the diagnosis of MS and NMOSD were developed and validated in populations with ethnic and environmental backgrounds distinct from what is observed in the Brazilian population, which might compromise the sensitivity and specificity of the criteria. Brazilian neurologists ought to be mindful to identify “red-flags” for atypical demyelinating syndromes and systematically rule out differential diagnoses, including endemic infectious diseases such as HLTV I/II and schistosomiasis.

Table 5.
Demographic, clinical, MRI and CSF features of demyelinating diseases of the central nervous system.

Role of novel biomarkers

Optical coherence tomography (OCT) is an imaging technique which uses infrared light in a similar manner to that of the ultrasound to measure different biological tissue's backscatter, getting micrometer-resolution images. When used in the retina, it allows the reconstruction of tomographic maps and quantification of axons of the retinal nerve fiber layer (RNFL) and neurons of the macular ganglion cell layer (mGCL)1212. Alonso R, Gonzalez-Moron D, Garcea O. Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult Scler Relat Disord. 2018 May 1;22:P77-82. https://doi.org/10.1016/j.msard.2018.03.007
https://doi.org/10.1016/j.msard.2018.03....
. OCT has consistently been used to screen for subclinical optical abnormalities in patients with demyelinating disorders, however data shows associations between reduced RNFL/mGCL and neurodegeneration with correlations to types of MS, disability and cognitive impairment1212. Alonso R, Gonzalez-Moron D, Garcea O. Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult Scler Relat Disord. 2018 May 1;22:P77-82. https://doi.org/10.1016/j.msard.2018.03.007
https://doi.org/10.1016/j.msard.2018.03....

13. Toledo J, Sepulcre J, Salinas-Alaman A, García-Layana A, Murie-Fernandez M, Bejarano B, et al. Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis. Mult Scler. 2008 Aug 1;14(7):906-12. https://doi.org/10.1177/1352458508090221
https://doi.org/10.1177/1352458508090221...

14. Garcia-Martin E, Ara JR, Martin J, Almarcegui C, Dolz I, Vilades E, et al. Retinal and optic nerve degeneration in patients with multiple sclerosis followed up for 5 years. Ophthalmology. 2017 May 1;124(5):P688-96. https://doi.org/10.1016/j.ophtha.2017.01.005
https://doi.org/10.1016/j.ophtha.2017.01...
-1515. Lambe J, Fitzgerald KC, Murphy OC, Filippatou AG, Sotirchos ES, Kalaitzidis G, et al. Association of spectral-domain OCT with long-term disability worsening in multiple sclerosis. Neurology. 2021 Apr 20;96(16):e2058-69. https://doi.org/10.1212/WNL.0000000000011788
https://doi.org/10.1212/WNL.000000000001...
. In addition, distinct OCT patterns can be used as diagnostic biomarkers aiding in the differential diagnosis of MOGAD from other demyelinating disorders1616. Narayan RN, McCreary M, Conger D, Wang C, Greenberg BM. Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients. Mult Scler Relat Disord. 2019 Feb 1;28:86-90. https://doi.org/10.1016/j.msard.2018.11.026
https://doi.org/10.1016/j.msard.2018.11....
,1717. Chen JJ, Sotirchos ES, Henderson AD, Vasileiou ES, Flanagan EP, Bhatti MT, et al. OCT retinal nerve fiber layer thickness differentiates acute optic neuritis from MOG antibody-associated disease and multiple sclerosis. Mult Scler Relat Disord. 2022 Feb 1;58:103525. https://doi.org/10.1016/j.msard.2022.103525
https://doi.org/10.1016/j.msard.2022.103...
.

Neurofilaments (Nf) are structural proteins involved in the radial growth and stability of neurons. Studies have demonstrated that Nf-l has a value as a scientifically useful biomarker of disease activity and therapy effectiveness of groups of patients with inflammatory diseases of the CNS, such as multiple sclerosis and clinically isolated syndrome1818. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018 Oct;14(10):577-89. https://doi.org/10.1038/s41582-018-0058-z
https://doi.org/10.1038/s41582-018-0058-...

19. Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, et al. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis. Eur J Neurol. 2017 May;24(5):703-12. https://doi.org/10.1111/ene.13274
https://doi.org/10.1111/ene.13274...

20. Kuhle J, Kropshofer H, Haering DA, Kundu U, Meinert R, Barro C, et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019 Mar 5;92(10):e1007-15. https://doi.org/10.1212/WNL.0000000000007032
https://doi.org/10.1212/WNL.000000000000...

21. Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, et al. Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-70. https://doi.org/10.1002/ana.24954
https://doi.org/10.1002/ana.24954...
-2222. Siller N, Kuhle J, Muthuraman M, Barro C, Uphaus T, Groppa S, et al. Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler. 2019 Apr 1;25(5):678-86. https://doi.org/10.1177/1352458518765666
https://doi.org/10.1177/1352458518765666...
. It is currently not commonly used in clinical practice, as its measure is modulated by body-mass index (BMI), age, and comorbidities which compromise the definition of fixed cutoffs and individually pathological levels of Nf-l2323. Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, Maceski A, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022 Mar 1;21(3):P246-57. https://doi.org/10.1016/S1474-4422(22)00009-6
https://doi.org/10.1016/S1474-4422(22)00...
. Recent data has shown that Nf-l levels can be clinically employed to predict disease activity and disease-modifying therapy effectiveness in the real world setting on an individual level if percentiles and Nf-l Z scores are used2323. Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, Maceski A, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022 Mar 1;21(3):P246-57. https://doi.org/10.1016/S1474-4422(22)00009-6
https://doi.org/10.1016/S1474-4422(22)00...
. Nonetheless, the description is new and the practice still not widespread.

Glial fibrillary acidic protein (GFAP) is a principal intermediate filament that forms the astrocyte cytoskeleton and is regarded as a biomarker of astrocyte injury2424. Watanabe M, Nakamura Y, Michalak Z, Isobe N, Barro C, Leppert D, et al. Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD. Neurology. 2019 Sep 24;93(13):e1299-311. https://doi.org/10.1212/WNL.0000000000008160
https://doi.org/10.1212/WNL.000000000000...
. Evidence describes its role as a potential diagnostic and prognostic biomarker in NMOSD, a known astrocytopathy, however its use is still currently limited to scientific purposes2525. Chang X, Huang W, Wang L, ZhangBao J, Zhou L, Lu C, et al. Serum neurofilament light and GFAP are associated with disease severity in inflammatory disorders with aquaporin-4 or myelin oligodendrocyte glycoprotein antibodies. Front Immunol. 2021 Mar 16;12:647618. https://doi.org/10.3389/fimmu.2021.647618
https://doi.org/10.3389/fimmu.2021.64761...
,2626. Aktas O, Smith MA, Rees WA, Bennett JL, She D, Katz E, et al. Serum glial fibrillary acidic protein: a neuromyelitis optica spectrum disorder biomarker. Ann Neurol. 2021 May;89(5):895-910. https://doi.org/10.1002/ana.26067
https://doi.org/10.1002/ana.26067...
.

DISCUSSION

Acquired demyelinating disorders lead to a plethora of clinical syndromes which are common among distinct nosologies. In the past 20 years, anti-aquaporin 4 antibodies (AQP4-IgG), anti-MOG antibodies (MOG- IgG) and their associated disease entities, AQP-4 IgG NMOSD and MOGAD, were described. Since then, making a differential diagnosis between the most prevalent acquired demyelinating disorders has become more challenging, especially in places where environmental and genetic conditions are distinct to those of the settings where studies guiding diagnostic criteria were carried out.

A methodical approach to the diagnostic process can aid in achieving timely accurate diagnoses. In addition to a thorough medical history and neurological examination, biomedical and imaging data can provide crucial information to aid in identifying each disease. Although clinical phenotypes often overlap, integrated analysis of demographic, clinical, biomedical, and imaging data is particular to each disease and therefore should be interpreted together.

As the field further develops, new technologies and biomarkers are systematically being studied and translated from the bench to the bedside. For now, it is suggested that neurologists examine the validity, specificity, and sensitivity for individual use of each new diagnostic tool before applying it in their routine diagnostic practice.

In conclusion, a comprehensive analysis of the diagnostic workup should be performed to obtain a differential diagnosis of an acquired demyelinating disorder. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.

References

  • 1. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010 May;9(5):520-32. https://doi.org/10.1016/S1474-4422(10)70064-8
    » https://doi.org/10.1016/S1474-4422(10)70064-8
  • 2. Pereira ABCNG, Lacativa MCS, Pereira FFCC, Alvarenga RMP. Prevalence of multiple sclerosis in Brazil: a systematic review. Mult Scler Relat Disord. 2015 Nov 1;4(6):572-9. https://doi.org/10.1016/j.msard.2015.08.004
    » https://doi.org/10.1016/j.msard.2015.08.004
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    » https://doi.org/10.1177/2055217317730098
  • 4. Lana-Peixoto MA, Talim NC, Pedrosa D, Macedo JM, Santiago-Amaral J. Prevalence of neuromyelitis optica spectrum disorder in Belo Horizonte, Southeast Brazil. Mult Scler Relat Disord. 2021 May 1;50:102807. https://doi.org/10.1016/j.msard.2021.102807
    » https://doi.org/10.1016/j.msard.2021.102807
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    » https://doi.org/10.1177/1352458515572406
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    » https://doi.org/10.1177/1756286420945135
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    » https://doi.org/10.3389/fneur.2018.00217
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    » https://doi.org/10.1016/j.msard.2018.07.026
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    » https://doi.org/10.1016/S1474-4422(17)30470-2
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    » https://doi.org/10.1212/WNL.0000000000007077
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    » https://doi.org/10.1016/j.msard.2018.03.007
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    » https://doi.org/10.1177/1352458508090221
  • 14. Garcia-Martin E, Ara JR, Martin J, Almarcegui C, Dolz I, Vilades E, et al. Retinal and optic nerve degeneration in patients with multiple sclerosis followed up for 5 years. Ophthalmology. 2017 May 1;124(5):P688-96. https://doi.org/10.1016/j.ophtha.2017.01.005
    » https://doi.org/10.1016/j.ophtha.2017.01.005
  • 15. Lambe J, Fitzgerald KC, Murphy OC, Filippatou AG, Sotirchos ES, Kalaitzidis G, et al. Association of spectral-domain OCT with long-term disability worsening in multiple sclerosis. Neurology. 2021 Apr 20;96(16):e2058-69. https://doi.org/10.1212/WNL.0000000000011788
    » https://doi.org/10.1212/WNL.0000000000011788
  • 16. Narayan RN, McCreary M, Conger D, Wang C, Greenberg BM. Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients. Mult Scler Relat Disord. 2019 Feb 1;28:86-90. https://doi.org/10.1016/j.msard.2018.11.026
    » https://doi.org/10.1016/j.msard.2018.11.026
  • 17. Chen JJ, Sotirchos ES, Henderson AD, Vasileiou ES, Flanagan EP, Bhatti MT, et al. OCT retinal nerve fiber layer thickness differentiates acute optic neuritis from MOG antibody-associated disease and multiple sclerosis. Mult Scler Relat Disord. 2022 Feb 1;58:103525. https://doi.org/10.1016/j.msard.2022.103525
    » https://doi.org/10.1016/j.msard.2022.103525
  • 18. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018 Oct;14(10):577-89. https://doi.org/10.1038/s41582-018-0058-z
    » https://doi.org/10.1038/s41582-018-0058-z
  • 19. Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, et al. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis. Eur J Neurol. 2017 May;24(5):703-12. https://doi.org/10.1111/ene.13274
    » https://doi.org/10.1111/ene.13274
  • 20. Kuhle J, Kropshofer H, Haering DA, Kundu U, Meinert R, Barro C, et al. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019 Mar 5;92(10):e1007-15. https://doi.org/10.1212/WNL.0000000000007032
    » https://doi.org/10.1212/WNL.0000000000007032
  • 21. Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, et al. Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-70. https://doi.org/10.1002/ana.24954
    » https://doi.org/10.1002/ana.24954
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    » https://doi.org/10.1177/1352458518765666
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Publication Dates

  • Publication in this collection
    12 Aug 2022
  • Date of issue
    May 2022

History

  • Received
    16 Mar 2022
  • Accepted
    29 Apr 2022
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