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Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers

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Abstract

Background and aims

Most patients with multiple sclerosis presenting with a relapsing–remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1–2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis.

Methods

We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement.

Results

From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers.

Conclusion

To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.

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Abbreviations

BAEPs :

Brainstem auditory evoked potentials

CCL :

Chemokine ligand

CHI3L1 :

Chitinase 3 Like 1

CIS :

Clinically isolated syndrome

CNS :

Central nervous system

CSF :

Cerebrospinal fluid

cTBS :

Continuous theta burst stimulation

CXC :

Chemokine CXC motif ligand

DMTs :

Disease-modifying treatments

EDSS :

Expanded disability status scale

EGF :

Epidermal growth factor

EPs :

Evoked potentials

FOXP3 :

Forkhead box P3

GEPS :

Global evoked potential score

GFAP :

Glial fibrillary acidic protein

HCs :

Healthy controls

HGF :

Hepatocyte growth factor

ICF :

Intracortical facilitation

IFN :

Interferon

IL :

Interleukin

ISI :

Interstimulus interval

iTBS :

Intermittent theta burst stimulation

LAG-3:

Lymphocyte activation gene 3

LICI :

Long interval intracortical inhibition

LTD :

Long-term depression

LTP :

Long-term potentiation

mEPS :

Multimodal evoked potential scores

MEPs :

Motor evoked potentials

miRNA :

Micro RNA

mRAGE :

Membrane receptor for advanced glycation end products

MRI :

Magnetic resonance imaging

MS :

Multiple sclerosis

MSSS :

Multiple sclerosis severity scale

M1 :

Primary motor cortex

NAWM :

Normal-appearing white matter

NfH :

Neurofilament heavy chain

NfL :

Neurofilament light chain

NfM :

Neurofilament medium chain

OCBs :

Oligoclonal bands

PAS :

Paired associative stimulation

PBMCs :

Peripheral blood mononuclear cells

PPMS :

Primary progressive multiple sclerosis

PRISMA :

Preferred reporting items for systematic reviews and metanalyses

RRMS :

Relapsing–remitting multiple sclerosis

SEPs :

Sensory evoked potentials

SICF :

Short-interval intracortical facilitation

SICI :

Short-interval intracortical inhibition

Simoa :

Single molecule array technique

SPMS :

Secondary progressive multiple sclerosis

STDT :

Somatosensory temporal discrimination threshold

TBS :

Theta burst stimulation

TGF :

Transforming growth factor

TGM6 :

Transglutaminase-6

Th :

T helper

TIM-3 :

T-cell immunoglobulin and mucin domain-containing 3

TMS :

Transcranial magnetic stimulation

TNF :

Tumor necrosis factor

Treg :

Regulatory T cells

T25FWT :

Timed 25-foot walk test

VEGF :

Vascular endothelial growth factor

VEPs :

Visual evoked potentials

9HPT :

9-Hole peg test

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Acknowledgements

We thank Melissa Kerr for the English language editing.

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Authors and Affiliations

  1. Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy

    Gina Ferrazzano, Sebastiano Giuseppe Crisafulli, Viola Baione, Matteo Tartaglia, Marco Frontoni, Marta Altieri, Flavia Pauri, Enrico Millefiorini & Antonella Conte

  2. Multiple Sclerosis Center, San Filippo Neri Hospital, Rome, Italy

    Antonio Cortese

  3. IRCCS Neuromed, Pozzilli, IS, Italy

    Antonella Conte

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  1. Gina Ferrazzano
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  2. Sebastiano Giuseppe Crisafulli
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Ferrazzano, G., Crisafulli, S.G., Baione, V. et al. Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers. J Neurol 268, 3626–3645 (2021). https://doi.org/10.1007/s00415-020-09964-4

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  • DOI: https://doi.org/10.1007/s00415-020-09964-4

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